This paper communicates the most relevant findings on renal cell carcinoma (RCC) presented at the 2006 annual meetings of the European Association of Urology (EAU), American Urological Association (AUA), and the American Society of Clinical Oncology (ASCO) and discussed during a closed meeting in Marbella in October 2006. Furthermore, the attendees’ opinions on a representative clinical case study were assessed using interactive voting and experts in the field commented on the results.
The most relevant new findings were selected by urologic experts in the field of RCC.
With regard to treatment of localised RCC, partial nephrectomy remains relatively uncommon, even for small tumours (<4
Relevant new data on surgical and minimally invasive treatment of localised disease and promising systemic treatments for advanced RCC were presented at the 2006 urologic/oncologic meetings.
Keywords: Angiogenesis inhibitors, Cryoablation, Partial nephrectomy, Radiofrequency ablation, Renal cell carcinoma, Sorafenib, Sunitinib, Temsirolimus.
Cancers of the renal parenchyma, also known as renal cell carcinomas (RCCs), account for just under 2% of all cancers worldwide. Although RCC is a relatively rare cancer, its incidence, as well as its associated mortality rates, have been increasing over the past 50 yr , , , and . A significant part of this apparent increase is believed to result from the wider application of imaging techniques such as ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI), leading to a rise in the number of incidentally diagnosed RCCs . However, data from American studies showed that, besides an increase in presymptomatic localised tumours, there has also been an increase in locally advanced and distant metastatic RCCs, suggesting that advanced imaging techniques are not the sole contributors to the rapidly increasing incidence , , and .
Prognosis for patients with RCC varies considerably depending on the stage of disease at diagnosis. According to the Surveillance Epidemiology and End Results (SEER) database, about 70–80% of the patients present with localised disease, which is associated with an 89.9% 5-yr survival rate. However, the 5-yr survival rate in patients with locally advanced disease drops to 61%, whereas patients with distant metastatic disease have only a 9% 5-yr survival rate .
These poor survival rates indicate that current therapies are insufficient, especially for patients with advanced disease characteristics. Over the past few years, however, increasing knowledge about the molecular and genetic basis of RCC has stimulated the development of novel and more targeted treatment strategies. Furthermore, advances in surgical techniques may favour a more conservative treatment for patients with localised disease.
This paper comprises the latest highlights on kidney cancer presented at the 2006 urologic and oncologic annual meetings of the European Association of Urology (EAU) in Paris, the American Urological Association (AUA) in Atlanta, and the American Society of Clinical Oncology (ASCO) also in Atlanta. A selection of abstracts from these congresses were discussed at a closed expert meeting “New Horizons in Urology” in Marbella. In addition, participants at this meeting were engaged in an interactive voting procedure to assess their opinions on a representative clinical case study and experts in RCC commented on the results.
2. Treatment of localised disease
Treatment approaches for RCC depend on disease stage at presentation. The standard treatment for patients who are diagnosed with local RCC and who have two functioning kidneys is radical nephrectomy (RN). However, advances in surgical and imaging techniques over the past several years have created the possibility of applying nephron-sparing surgery or minimally invasive treatment strategies as alternatives to invasive RN .
2.1. Partial nephrectomy
Partial nephrectomy (PN) was first advocated in patients with a single kidney or a nonfunctioning contralateral kidney or in patients with or at risk for bilateral RCC. However, the current EAU guidelines on RCC also recommend PN for patients with a solitary tumour <4
Even though it has been demonstrated that PN in patients with a tumour <4
2.2. Minimally invasive techniques
New and progressive minimally invasive techniques such as laparoscopic cryoablation (LCA) or radiofrequency ablation (RFA) are emerging as alternative therapies for the treatment of small RCCs, especially for patients who are poor candidates for surgical interventions. These procedures consist of the insertion of a probe into the tumour using real-time imaging guidance by ultrasonography, CT, or MRI, and then destroying the tumour with cold (LCA) or heat (RFA) . Although these techniques have the disadvantage compared to traditional surgery in that histopathologic confirmation of complete tumour resection with clear margins is not possible, a great deal of attention was paid to both of these minimally invasive techniques at this year's urologic meetings.
LCA is an emerging technique for a select group of patients who preferentially have small (<4
A study presented at AUA 2006 annual meeting assessed the long-term oncologic outcomes in patients treated with LCA between September 1997 and September 2005 . Sixty patients treated with LCA completed at least 5 yr of follow-up (median: 72 mo) that consisted of MRI on postoperative day 1, at 3, 6, and 12 mo, and annually from then on. Furthermore, a needle biopsy was performed in conjunction with the 6-mo scan. The initial indication for treatment was a solitary sporadic RCC in 73% of the patients, with a mean tumour size of 2.3
Even though the former study may support the use of LCA in a select group of patients, a matched-cohort study by O’Malley and colleagues comparing laparoscopic PN (LPN) and LCA did not favour the use of LCA over LPN for the treatment of small peripheral tumours . In this study, 15 patients who had LCA between May 2003 and July 2005 were compared with an age- and tumour size-matched cohort of 15 patients from a pre-existing database of 104 patients who underwent LPN between July 2002 and July 2005. Surgical outcomes between the two groups were similar; only the LPN group had a significantly longer operating time (p
At the closed meeting in Marbella, however, some concerns were expressed regarding this study. It was emphasised that it was a retrospective, small-scale study with a short-term follow-up period and that rather long-term data from a head-to-head prospective large-scale study are needed to bring more insights on whether or not LPN should be favoured above LCA.
Another minimally invasive technique that is currently being evaluated is RFA, which has gained more popularity in recent years. Although RFA was initially proposed for patients unfit for (laparoscopic) surgery due to a poor performance status (American Society of Anesthesiologists [ASA] score of 3 or 4), serious comorbidities, minor renal function, or high-risk for developing additional RCCs, a study presented at the AUA 2006 annual meeting assessed this technique in healthy ASA 1 and 2 patients , , and . Thirty-seven patients with a mean age of 57 yr (range: 20–84 yr) and a mean tumour size of 2.2
Although these and prior results show that treatment of small RCCs with RFA is feasible and safe in both ASA 1 or 2 and ASA 3 or 4 patients, clearly more data from larger-scale studies with long-term follow-up are needed to further validate these results , , and . It has been suggested that for long-term evaluation of the ablative properties and completeness, more adequate long-term oncologic outcomes should be assessed and preferentially compared with PN as a standard .
In this respect, a study, presented at the AUA 2006 annual meeting, compared intermediate outcomes of patients diagnosed with cT1a renal tumours who were treated with PN or RFA . Of all patients treated for cT1a RCC between July 1994 and May 2005, 141 patients were selected for this study because they did not present with bilateral synchronous or metachronous tumours, metastatic disease, or hereditary RCC. From these, 53 (37.6%) underwent open or laparoscopic PN, whereas the remaining 88 (62.4%) had either percutaneous or laparoscopic cryoablation. The mean age was 56.5 yr (range: 32–79 yr) in the PN group and 62.6 yr (range: 18–85 yr) in the RFA group, and mean follow-up periods were 3.4 yr (range: 1.3–8.8 yr) and 1.4 yr (range: 6 wk to 3.5 yr), respectively. There were four incomplete ablations and three recurrences in the RFA group. Of these, four had a successful re-ablation, one died of heart failure, and two underwent nephrectomy, revealing residual RCC in one and benign tumour in the other. In the PN group, on the other hand, there were two patients with recurrences of whom one had a new enhancing renal mass and the other was diagnosed with advanced RCC that was treated with nephrectomy. The recurrence-free probability at 3 yr was 97.5%
Overall, it can be stated that RN remains the gold standard treatment for localised disease. However, during recent years, there has been a growing tendency towards nephron-sparing and less invasive laparoscopic surgery because these procedures clearly improve the patient's postoperative quality of life. Given the rising importance of laparoscopic surgery for the treatment of RCC, it was indicated at the “New Horizons in Urology” meeting in Marbella that new residents in urology should be proficient in laparoscopic surgery on completion of their training. With regard to minimally invasive techniques such as LCA and RFA, so far, no studies are available evaluating the long-term oncologic outcomes of these rather new procedures. However, it is believed that these techniques are promising and efforts should be undertaken for further optimalisation.
During the closed expert meeting “New Horizons in Urology” held in 2006, the participants were engaged in an interactive voting procedure to assess their treatment preference on a representative case study suggestive of kidney cancer. The results were discussed and experts in the field of RRC offered comments.
A 61-yr-old woman with hypertension and type 2 diabetes presented to the physician complaining of left flank pain for the last 2 wk. An ultrasound examination showed a peripheral renal mass of approximately 3.5
With this background information in mind, the participants from the closed meeting were asked to choose a treatment strategy through interactive voting. The results from this voting procedure are shown in Fig. 4. Forty percent of the participants chose open PN, whereas a surprising 30% went for its laparoscopic counterpart. The remaining persons chose RN, either open or laparoscopic (Fig. 4).
Thus, the majority of the attendees decided on performing an open PN and this procedure was actually performed on the patient. However, the experts reflected on the fact that a large proportion of the urologists voted for LPN. Although a progressive shift from open to laparoscopic surgery has been seen over the past few years, performing LPN remains a challenging procedure due to the risk of converting PN into RN because of technical issues. Therefore, training of new residents should focus on this issue and it was advocated by the author that on completion of their residency, urologists should be able to perform laparoscopic surgery. Finally, the remark was made that still 30% of the attendees to the closed meeting opted for RN. Given the data currently available on treatment of small renal masses, this was regarded as over-treatment by some of the experts.
3. Treatment of advanced and metastatic disease
To date, treatment of metastatic RCC with surgical intervention or immunotherapy has been largely unsuccessful. In patients with limited metastases, nephrectomy and resection of metastatic lesions may be a suitable therapy. Generally, however, the cancer is too widespread and the standard treatment for those patients is immunotherapy with interferon-α (IFN-α) or interleukin 2 (IL-2). Unfortunately, IFN-α or IL-2 administered as a single agent only achieves response rates of 8–26% and 7–23%, respectively . These poor outcomes have emphasised the need for new and more effective treatment strategies.
Over the past several years, the understanding of the molecular and genetic basis of RCC has led to the development of new agents for the treatment of metastatic RCC. Although RCC has several histologic subtypes, 70–80% of all tumours contain clear-cell RCC (ccRCC) morphology of which both sporadic and hereditary forms are associated with mutations in the van Hippel-Lindau (VHL) tumour suppressor gene. Loss of the VHL protein function eventually leads to overexpression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), both of which promote tumour angiogenesis and by consequence contribute to the hypervascularisation of RCC . Therefore, novel developments in the treatment of RCC aimed at targeting the VEGF and PDGF pathways with the intention to reverse the physiologic consequences of losing the VHL protein function. In this respect, several new drugs have been developed of which sunitinib, sorafenib, and temsirolimus were extensively discussed at this year's urologic and oncologic congresses.
Sunitinib, also known as SU11248, is a small molecule receptor tyrosine kinase inhibitor (TKI) with both direct antiproliferative and antiangiogenic properties by targeting VEGF, PDGF, KIT, and FLT3 tyrosine kinases . Recently, promising results were obtained in two multicentre, phase 2 trials that assessed the clinical activity and safety of sunitinib as second-line therapy for patients with metastatic RCC who progressed after one prior cytokine therapy  and . In summary, 34–40% of the patients treated with sunitinib achieved a partial response and an additional 27–29% of the patients demonstrated stable disease for ≥3 mo. The median progression-free survival was 8.3–8.7 mo.
A phase 3 clinical trial of sunitinib versus INF-α as a first-line treatment of metastatic RCC was presented at the ASCO 2006 annual meeting  and has recently been published . Between August 2004 and October 2005, 750 patients with metastatic ccRCC were randomised in a 1:1 ratio to receive sunitinib (6-wk cycles: 4 wk 50
Sorafenib, formerly known as BAY 43-9006, is a novel bi-aryl urea initially developed as a specific inhibitor of Raf kinase. More detailed analysis showed that sorafenib also has significant activity against other TKIs involved in tumour progression and neoangiogenesis including VEGFR2 VEGFR3, PDGFR-β, FLT3, and c-KIT . So far, two phase 2 studies have shown the antitumour activity of sorafenib and at the EAU 2006 annual meeting results were presented from a double-blind, placebo-controlled phase 3 study , , and . These results were recently published . A total of 905 patients diagnosed with advanced ccRCC in whom one prior systemic treatment course had failed were randomised to receive continuous oral sorafenib twice daily or placebo added with the best supportive care. First interim analysis of 769 patients demonstrated that the median progression-free survival time was 24 wk for sorafenib compared to 12 wk for placebo, with a hazard ratio of 0.44 (p
Temsirolimus (CCI 779) is a specific inhibitor of mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that, through its role as key regulator of the cell cycle, presented itself as a potential target for antitumour therapy . In a phase 2 clinical trial by Atkins et al, 7% of the 111 patients with advanced RCC who were assigned to this single-agent study on temsirolimus obtained an objective response and a minor response was observed in 26% of the patients . The efficacy and safety of temsirolimus was further addressed in a three-arm, randomised, phase 3 study that was presented at the ASCO 2006 annual meeting . In this study, 626 patients with advanced RCC with no prior systemic therapy were randomised at a 1:1:1 ratio to arm 1 (IFN-α up to 18 MU subcutaneously twice/wk; n
Next to sorafenib, sunitinib, and temsirolimus, the monoclonal antibody bevacizumab has been evaluated for its use as second-line therapy in metastatic RCC as well. Although the results that have been gathered on these new drugs are promising, especially because they are more effective than cytokines in the treatment of metastatic RCC, clearly additional data are needed to further validate and confirm these results. Additionally, more research is needed to further improve the current drugs and to develop new therapeutic agents because, so far, no complete response is achieved with antiangiogenic drugs.
At the key urologic and oncologic congresses of 2006, many interesting and promising new data were presented. Although an increasing body of evidence supports the implementation of PN as a first-line treatment for localised disease, SEER data from the United States show that PN remains relatively uncommon, even in small RCCs (<4
A great deal of interest was also devoted to minimally invasive techniques. A large study with a 5-yr follow-up period demonstrated that LCA treatment was associated with a high cancer-specific 5-yr survival rate. However, it was suggested that, to achieve this kind of outcome, physicians should be proficient in performing laparoscopic surgery. Therefore, new residents should be qualified to master this technique on completion of their residency, not only to perform LCA, but also for RN and PN. Another study suggested that even though LCA is a good treatment option for small RCCs, especially in elderly people unfit for surgery, LPN should remain the preferred option as definitive treatment of small, sporadic renal tumours. Although RFA is normally reserved for patients at risk for surgery, a 2-yr follow-up study showed that this technique is also safe and feasible in patients with ASA status 1 or 2. Furthermore, a comparison was made between PN and RFA for treatment of cT1a RCC, which showed that both techniques have a comparable 3-yr outcome. Although these data on minimally invasive techniques seem promising, more large-scale, long-term data are needed to further confirm them.
Driven by the poor outcomes of surgical and cytokine-based treatment of advanced RCC and the progress made in elucidating the molecular and genetic basis of RCC, several new agents have been developed including sunitinib, sorafenib, and temsirolimus. It was shown that sunitinib is superior to IFN-α as first-line treatment for patients with advanced ccRCC. Furthermore, a large-scale phase 2 study demonstrated that sorafenib significantly prolongs the progression-free survival compared to placebo in patients previously treated for advanced RCC. Finally, it was demonstrated that single-agent temsirolimus, and not the combination therapy temsirolimus
Conflicts of interest
Francesco Montorsi is a paid consultant for Pfizer, Bayer, GSK, AMS, Pierre Fabre and Eli Lilly.
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Department of Urology, Università Vita Salute San Raffaele, Via Olgettina 60, 20132 Milan, Italy
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