 I'm Keri Konoski and this is Kidney Cancer News for July. Now, here's Bill Brough with a roundup of late-breaking news. Thank you, Keri. News from Boston and researchers at Beth Israel Deaconess Medical Center that an antibody helps a person's own immune system to battle cancer cells and shows increasing promise in reducing tumors in patients with advanced kidney cancer. Results of an expanded Phase 1 trial presented at the American Society of Clinical Oncologies annual meeting in Chicago showed that some patients treated with a fully human monoclonal antibody developed by Bristol Meyers Squibb had a positive response to the effort by the agent without some of the debilitating side effects common to earlier immunotherapies. Now highlights from the recent 2012 European International Kidney Cancer Symposium in Vienna, Austria. And I've been asked to speak on the most conservative end of the treatment spectrum in first-line metastatic renal cell carcinoma. So we've heard already at this meeting that renal cell carcinoma is a heterogeneous disease. There are nine histopathological subtypes, but increasingly we're recognizing that within those histopathological subtypes and furthermore within individual patients there's marked genomic variation and the presence of tumor heterogeneity. And it seems likely that the histopathological variation and genomic variation gives rise to diverse biological behavior in this disease. And that translates into the clinic and there's a lot of anecdotal evidence for differing clinical subsets of patients, those with an aggressive tempo of disease and those within a very indolent pace of disease, particularly those patients with lung metastases only. Although there have been huge advances in the systemic treatment for metastatic renal cell carcinoma, treatments remain palliative and therefore chronic and they're moderately toxic. And so our practice at least in the UK has been to defer drug therapy until there is a clinically relevant burden of disease. And the main argument for this has been from the point of view of patient quality of life. And this is a practice which I think is widespread in other tumor types as well, but there is actually very little evidence to tell us that this is a safe approach. In indolent lymphoma there is prospective evidence for a watchful waiting approach, but the difference between indolent lymphoma and renal cell carcinoma is that Rituximab is relatively non-toxic. It has been suggested from a randomized discontinuation trial of seraphonib that patients are not disadvantaged by a brief time of treatment. But we wanted to try and more formally evaluate our practice, and we particularly wanted to do this in the kinase inhibitor era. And so our starting point was looking at patients who had been treated with synitinib between 2005 and 2010 at the Royal Marston and at Guy's and St Thomas's Hospital. And within that group of synitinib treated patients we identified those who had had a planned period of observation prior to kinase inhibitor therapy because of asymptomatic or slowly progressive disease. And our primary aim was to determine the progression free survival or clinical outcomes of those patients once they actually started first line systemic therapy. It was a very simple study schema. We retrospectively identified patients who had been diagnosed with metastatic disease and in who there had been a clinical decision to observe initially. That was 62 patients out of about 200 treated with synitinib. We wanted to measure the observation period and then look at the progression free survival and overall survival of those patients once they had started treatment. And although we looked at patients treated with synitinib in that time period, some of these patients had previously had been treated with interferon after a period of observation. The study cohort was very typical for an advanced renal cell carcinoma population. Mostly male patients mostly had clear cell carcinoma and the mean age of diagnosis was 57 years. About half had metastasectomy at some point and radiotherapy and not surprisingly almost all were in the favourable risk group as defined by MSKCC's score. And I should say also that almost all of these patients had had an refractomy and an interval between curative surgery and the diagnosis of metastatic disease. Progression of disease on imaging or clinician anxiety was the most common reason that treatment was initiated and a third of patients developed symptoms from their disease and were started on treatment for that reason. Here the time on observation varied very widely but the average time on observation for these patients was 18 months. I was somewhat surprised to see the difference in observation time between synitinib and interferon. I would have thought with the advent of a new effective treatment there would have been more enthusiasm for starting treatment earlier and I can't easily explain these figures but that is one of the limitations of a retrospective review. The clinical outcomes for these patients were reassuring. The median progression free survival time for patients on synitinib, 39 patients was 9 months and for interferon was 6.7 months and overall the median progression free survival was 9 months. And the overall survival data also was comparable for this general population. So overall there was a median overall survival of 25 months. And particularly in the interferon group there was a very prolonged survival but again this is a retrospective review clearly limited by selection. A brief comment about toxicity from synitinib, it was very common and actually hospital admission for synitinib related toxicity was required in 13% of patients and most patients ended up having a dose reduction for toxicity. So in this selected cohort of patients with indolent, favorable or intermediate prognosis metastatic renal cell carcinoma, first line systemic therapy was deferred by a mean of over one year. And once patients started on synitinib treatment, the median progression free survival and overall survival times were comparable to those observed in the larger prospective trials of synitinib. This is a retrospective analysis, the confidence intervals for the data were very wide and it's impossible to exclude selection bias. And I think although we can cautiously conclude that in this particular group of patients, deferring therapy seems a reasonable practice. We aren't in any way enlightened as to what defines that group of patients. And for this reason we think that prospective evaluation of surveillance as a treatment strategy is critical. And we hope that it might help us to define that group of patients for whom delayed systemic therapy is ideal. And I think that the major challenge of treating metastatic renal cell carcinoma exists in this treatment strategy that we have no molecular means by which to select patients for treatment. We've assumed that deferring systemic therapy will have a positive impact on quality of life. But it's possible that patient anxiety from not having treatment might have the opposite effect. And so studying this prospectively would allow longitudinal assessment of quality of life. And it might allow us to perform some of that much needed translational research not only with tissue collection but looking for predictive biomarkers with less invasive sampling means. Importantly, most developed countries are facing a situation of drug rationing and the strategy of observing patients in this population might have significant health economic benefits. And for all of these reasons, we wholly support a prospect of observational study which is currently recruiting and being led by Dr Rene. Thank you for your time and to my co-investigators and colleagues at the Royal Marsden Hospital and at Guy's and St Thomas's and thank you for the opportunity to speak today. I would like to start this presentation thanking the scientific committee for this kind invitation for the Saturn project on behalf of all the members of the Saturn project. Sorry. I am the coordinator of this Italian project together with Nicola Longo and Alchiede Simonato and this is a multi-center retrospective national study including data coming from 16 referral Italian centers and we included in this database all the patients who underwent partial or radical nephrectomy for localized or advanced RCC in the period between 1995 and 2007. And we performed for all cases the follow-up in 2009 and at this moment we have the possibility to evaluate the results in more than 5,000 cases. In one of the first paper of this experience published in 2010 by my colleagues, Giacomo Novara in the European neurology about the validation of the 2009 version of the TNMS edging system, we noted that histologic subtypes turned out to be an independent predictors of cancer-specific survival at multivariable analysis. And therefore this observation support our convention and our idea that renal cell carcinomas are different types of tumors with different morphology, with different molecular characteristics and at the same time with different cytogenetic findings. And this concept is always present and is considered also when we look at the different response of these tumoristotypes for medical therapy and usually the most important guidelines like NCCN consider papillaria RCC in the big folder of the no-clear cell histology. But we must pay attention when we put together all the different tumoristotypes in the no-clear cell folders because as you can see in this slide, we have chromophobic RCC, papillaria RCC, but also unclassified and bellini tumor with prognosis significantly worse in comparison with papillary and chromophobic histological subtypes. And the same consideration where, from this paper published in 2008 in the BJU International from Capitania and Coorg, as you can see also in this experience, the survival of papillary RCC is in the middle between chromophobic and the clear cell RCC. And again, when we look at the most important paper published in the literature in this field, we can observe the percentages of the five-year cancer-specific survival is in the middle between the worst prognosis represented by clear cell RCC and the best prognosis represented by chromophobic. But I ask you to pay attention to these differences in the five-year cancer-specific survival between these two studies, one coming from Mayo Clinic after slight revision process and another one that is a multistitutional study from European centers in which we observed a five-year cancer-specific survival significantly lower, but without slight revision of the cases. And this is an important message because in these little studies published by myself in 2006, we demonstrated that for papillary RCC, the originally a senior cases, the cancer-specific survival is different in comparison with the cases as seen as papillary RCC after slight revision. And this is very important above all when we consider it in the retrospective analysis, cases observed and treated before 1997. And for this reason, we started with this study with a certain project, including cases observed and treated from 1997. And this is the publication in the European, in the BJU Urology, about the prognostic factors in papillary RCC. Our task was to evaluate the prognostic factors in 577 cases observed in this multistitutional experience. As you can see, looking at the characteristics of patients, we have a mean age of 62 years. The majority of this present showed a symptomatic disease and we performed in 62% of cases radical nephrectomy, in 32 cases, an elective nephron-sparing surgery, and in 6% of cases, an imperative nephron-sparing surgery. But very important when we look at the pathological characteristics of this tumor, we observed that 80% of the cases were localized tumors and only 10% of the cases we have patients with lymph node involvement or distant metastasis at presentation. And very important is that the 30% of cases were grade three or four according to form and classification, and this patient can be considered as a type two according to the classification of the lung and the e-ball. And concerning oncological outcomes, in this experience, we have a medium follow-up of 39 months with 464 patients alive and this is free with a medium follow-up of 42 months. 40% of cases had a disease progression. 11% of cases died for the disease and 5% of the cases died for auto-care causes, not correlated with kidney cancer. Looking at the recurrence of free survival, we observed that a five-year recurrence free survival of 85.5% of the cases and a 10-year recurrence free survival was 73% of the cases. And when we analyze our data according to univariable and multivariable analysis, we showed that pathological stage was not statistically significant at the multivariable analysis and only lymph node involvement present of distant metastasis and the nuclear grading turned out to be independent predictors of recurrence free survival in this patient. This is a very important message above all for the TNM classification because I am convinced that the majority of the information coming from the literature are coming from clear cell RCC and perhaps our TNM system works and works very well for clear cell RCC but probably the situation for papillario-chromophobe or otter tumoristotypes is completely different and therefore this could be considered in the future. Otter very important message is grade one and grade two. As you can see, the survival is significantly different in comparison with grade three and grade four cancer. But the most important prognostic factors are represented by lymph node involvement. As you can see, patient with lymph node involvement at the diagnosis showed a five year recurrence free survival of 26.8% of the cases and also the patient with distant metastasis showed a similar five year recurrence free survival. What's about cancer specific survival? This is the survival curves showing the five years and 10 years cancer specific survival and at the multivariable analysis we had the same results that I showed before for recurrence free survival. Again, the only difference is that mode of presentation turned out to be an independent predictors of cancer specific survival. And as you can see, incidental tumor showed cancer specific survival significantly better in comparison with patient with local symptoms or above all with patient with systematic symptoms. Of course, our study had some study limitation. The first one is that this is a retrospective analysis. At the same time, we included data coming from 16 centers then this is a multi-surgeon series. The specimen was evaluated by multiple pathologists without slight revision and the treatment for disease recurrences was not standardized. And again, without slight review it was not possible for us to have seen correctly the subdivision of the papillary RCC in type one and type two according to the law and the IBLI classification. And it seems to be that this is important according to this paper published by UCLA showing that type one tumor is significantly better in comparison with type two. But I would like to ask you to pay attention when we use this subclassification between type two and type one because looking at the literature, this subtyping remains difficult and different percentages of type one and type two are reported in the published series. This means that it's very difficult for the pathologists correctly as seen the type two papillary and then we need to have very experienced pathologists to have correct evaluation of this parameter. Another important point that it was not evaluated in the Saturn project was the role of a nuclear grade. In this publication, some pathologists support the use of the nuclear or grading instead of the formal grade for papillary RCC. And in this more recent paper coming from the US, UCLA, Clate and Co-Works show that nuclear grading seems to be more predictive in comparison with the nuclear or grading as you can see looking at the different values of the concordance index. Another parameter that it was not evaluated because it was available only in small percentages of our cases was coagulative necrosis. As you can see in the experience of the Mayo Clinic coagulative necrosis for papillary RCC is not important. Vice versa, when we consider the experience of the UCLA necrosis turned out to be in papillary RCC and independent predictors of cancer specific survivor. Then in conclusion, I think that this data can demonstrate that papillary RCC is a low risk tumor recurrence and cancer related that after surgery. At the same time, we must pay more attention for patients with papillary RCC with lymph node involvement and the presence of distant metastasis and above all for patients with grade three and grade four and nuclear grading according to Foreman. More attention, we must pay for the correct allocation of the subtype and sub one and two in this category of tumors. And I think that to have more and more information and to better identify the characteristics of this tumor we must consider in the next future more studies including molecular and cytogenetic prognostic factors. Thank you so much for your attention. That's kidney cancer news for this month. I'm Keri Konoski wishing you good health.