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Notes from the 8th International Symposium
Patient advocates generously volunteered their time to take notes at the recent 8th International Kidney Cancer Symposium, in Chicago. These notes are intended to capture the essence of this important medical meeting and convey it in a way that is useful to patients, survivors, and their families. The first installment sumarizes the Saturday morning session.
Integration of Surgical and Systemic Therapy in Metastatic RCC
This session was opened by Dr. Bradley Leibovich who presented two cases on which the audience voted on methods to integrate surgery with systemic treatment interventions. The diversity of responses opened the way to consideration of the three discussions that followed.
Dr. Jorge Garcia discussed the role of neoadjuvant therapy in metastatic renal cell carcinoma. He pointed out that patients with resectable disease offer proof of concept, that resection has a place in metastatic disease. In patients seen as unresectable, surgery may still offer an opportunity to attempt to downstage, with surgery preceding systemic therapy. He suggested that using PKIs may downsize and impact distant metastases.
Dr. Allan H. Pantuck discussed debulking nephrectomy. He presented the theoretical rationale for debulking which include about a 1% chance of spontaneous regression of metastatic sites, the potential to improve performance status, reduction of tumor burden and removing source=2 0of future metastases as well as source of growth factors and cytokines. He also pointed out that debulking can be indicated for palliation of pain and other symptoms. He noted that there is a survival benefit to debulking. He said that whether or not to do a biopsy depends on what you have to offer. Dr. Pantuck said that cytoreductive nephrectomy for metastatic renal cell carcinoma is still the standard of care with the caveat that it is not appropriate for everyone. Careful selection is key. Four things need to be considered: fitness for surgery, type of symptoms, metastatic burden, planned therapy. He concluded by pointing out that cytoreductive therapy is not as successful for non-clear cell renal cell carcinoma as for clear cell and that this probably is because there is no systemic follow-up available.
Dr. Christopher Wood discussed the surgical management of metastatic renal cell carcinoma. He indicated five roles for surgical intervention: resection of nodal metastases, resection of isolated/limited metastatic disease, resection of loca l recurrence, surgical consolidation following systemic therapy and palliation of symptoms. He pointed out that in nodal disease, volume matters and that nodal disease together with distant metastases offers a dismal prognosis. He stated that lymph node dissection improves outcome for those with nodal disease and that a person with a solitary metastasis does better than one with multiple metastases. He made the following observations: lung and gland metastases have better outcomes than other metastases; adrenal and pulmonary metastases only have the most positive response to metastasectomy; pancreatic metastases seem indolent and very responsive to resection; liver metastases are problematic but, if single, resection can be very effective; wide resection can be very effective for bone metastases. For renal fossa recurrence, Dr. Wood suggested that systemic therapy and surgery is the best intervention and that margin of resection is very important. Dr. Wood stated that, overall, metastasectomy should be considered for all metastases. Timing matters and metastasectomy done at the time of nephrectomy is the best intervention. This is only proven for clear cell histology. The role in other histologies is unproven. When considering surgery versus system ic therapy plus surgery, there are important selection factors to be considered including size of tumor, presence of sarcomatoid features and margins. Dr. Wood offered data that surgery after IL2 is beneficial.
Dr. Tim Eisen reviewed the VEGFR-target treatments that are currently in trials which can be found at www.clinicaltrials.gov. He pointed out that VEGFR targeted therapy is looking for better efficacy and tolerability; understanding issues of inhibitory spectrum, dosing schedule, mechanisms of resistance, side effects; predictive markers. He also reviewed HIF(+) targeted treatments and AKT & MeT targeted t rials that are listed on www.clinicaltrials.gov. He noted that trials now involve single agents but that a possible role for combinations where synergy is key, that efficacy must be greater than toxicity, is being studied. www.clinicaltrials.gov also lists phase two trials combining Vorinostat alone or in combination with bevacizumab, sorafenib, or isotretinoin. Another novel therapy currently in phase II trial is botezomib, a proteasome inhibitor. Dr. Eisen discussed pathways of all of the agents in detail, affirming the complexity of treating renal cell carcinoma.
Dr. Yasuhisa Fujii discussed immunotherapy in the targeted therapy era. His focus was on the possible utility of interferon as a first-line therapy in sequential strategies. He noted that sunitinib is better than interferon except in a small subset of patients with sequential therapy. He discussed that bevacizumab and INF is better than INF alone but does have greater toxicity. He reviewed that the clinical challenges in rcc therapy are toxicity, cost, maintenance of treatment, development of resistance. He offered ICCA therapy: combination treatment using interferon, cimetidine, Cox 2 inhibitor, angiotension blocker. This is currently in prospective phase II trial in Japan. Dr. Fujii offered that ICCA is safe, cost-effective, comparable to targeted agents. He sees that there is still a place for this therapy in selected populations.
Timothy Kuzel presented an abstract on a phase 2 multi-center, randomized, open-label study of two dose levels of IMO-2055 in patients with metastatic or recurrent renal cell carcinoma.
He found that overall survival and progression-free survival rates compare well with established immune therapy regimens. The drug appears to be a tolerable treatment but with minimal benefit.
Dr. Daniel Cho spoke about PI3-Kinase/Akt inhibitors in renal cell carcinoma. He reminded us that this pathway is activated in 40 to 59% of rcc patients and that temsirolimus and everolimus have show activity in advanced RCC. Because PI3-Kinase/Akt regulate numerous kinases, transcriptional factors and other proteins besides mTOR, there may be greater efficacy in targeting upstream of mTOR. He gave a tutorial on the prosurvival activity of AKT. He discussed the lack of understanding of why mTOR inhibitors work in RCC. Dr. Cho indicated that Perifosine inhibits Akt activation and phase II trials had shown grade 3 and 4 toxicities to be very uncommon with this drug in patients with advanced RCC who had failed prior TKI therapy. Whereas Perifosine is an indirect inhibitor of Akt activation,20 five agents which directly inhibit the kinase activity of either PI3-K or Akt are now entering phase I clinical trials. Dr. Cho pointed out that pre-clinical experiments have supported the idea that inhibition of PI3-K/mTOR is superior to inhibition of mTORC1 alone so that further studies are required.
Dr. Thomas Hutson presented an abstract on a phase II study of perifosine in patients with metastatic RCC progressing after prior therapy with both a VEGFR inhibitor and a mTOR inhibitor. He indicated that perifosine appears to have clinical benefit in metastatic RCC in patients who failed both a prior VEGFR and mTOR inhibitor. Further randomized studies are being considered to evaluate perifosine’s clinical benefit as second or third line therapy of metastatic RCC. This may include combining perifosine with a mTOR inhibitor or perifosine vs a mTOR inhibitor.
Dr. Bernard Escudier discussed the potential role o f cMET inhibitors in RCC therapy. He noted that cMET is associate with hereditary papillary type 1 RCC. He then gave a tutorial on cMET biology and discussed three different cMET inhibitors that are being studied. He noted that the inhibition of cMET induces tumor shrinkage in papillary RCC. Several cMET inhibitors are bei ng lookd at including AMG 102, XL880 (GSK 1363089) and ARQ197. Questions regarding cMET to be addressed: Is activity restricted to cMET mutated tumors? Is cMET mutation occurring during the course of treatment? Is there any interaction between cMET and VEGF pathways? Thus, although cMET is a promising pathway in cancer and papillary type 1 RCC is an excellent model to test cMET inhibition, there remains significant work to be done in defining the role of cMET in RCC.
Dr. David McDermott presented an overview of ongoing trials with novel agents. He talked about the plethora of agents available for study and the importance of determining whether combination or sequential therapies are most helpful to patients. This remains the big issue facing treatment of RCC today: What to use when. He discussed the importance of novel endpoints being personalized care and complete response. He indicated that immune checkpoint inhibitors have the promise of addressing the geriatric patient with comorbidities. Dr. McDermott said that while advances in therapeutic intervention are important and promising, observation as a treatment approach also has a place in the spectrum.
Understanding the Biology of RCC
Dr. Michael Atkins presented a discussion of the molecular biology of resistance to VEGFR blockade as a critical obstacle to improved clinical outcomes. Therefore, the mechanisms of acquired resistance is a key to optimal combination therapy. He and his colleagues are working with animal models to better understand and intervene in this resistance. Animal testing needs to determine the mechanism of action before testing can begin in humans. He noted that this is a complicated and vexing problem but that he is confident the tools are in place to determine the underlying mechanisms and lead to the development of rational treatment approaches.
Dr. David Quinn discussed clinical definitions of targeted therapy resistance. He affirmed that the overriding question is the optimal sequence of therapy, observing that, currently, a lottery approach may prevail. Dr. Quinn outlined the remarkable increase in treatment options for RCC achieved in a short period of time from 1992 to 2009 when the options went from HDIL2 to a choice of six approved therapies with trials ongoing with other drugs. However, this rapid change has left many unanswered questions, including the optimal sequence of therapy. He noted that today in RCC, therapy is chronic with some control of stable disease in the presence of prevalent side effects. Sequential therapy is developing as the standard as combination therapy has not borne fruit. Long-term disease control with maintenance of health is a viable option. Dr. Quinn outlined that patients progress or fail in a number of ways so that mechanisms of resistance are very important to understand. Key questions to be looked at include is the target of the drug present in the patient; is the dose suboptimal; is there secondary resistance; would a drug holiday help or is it time to change to a different drug? When deciding whether to continue or switch, questions to be addressed include are the new lesions special; are complementary therapeutic approaches such as radiation therapy, surgery, cryo-ablation an option? Surgery and/or cytokine therapy may be curative in some patients. Beyond this, systemic therapy offers disease control and potentially prolonged survival. Development of personalized intervention must be underpinned with a molecular understanding of resistance.
Dr. Martin Gore discussed the clinical approach to the targeted therapy resistant patient. He said there is no curative therapy for 90% of metastatic RCC patients. Treatment is aimed at delaying death and giving good quality of life. One of the problems faced is target bypass. There are so many pathways that blockade becomes problematic. Sequencing seems to be the better approach than combinatorial but work is still being done on which sequence and when to change. There are currently four or five trials20working on sequencing. There is real value in slowing progression. Targeted therapies slow progression and that matters because that opens the potential to turn metastatic RCC to a chronic disease.
IN SUMMARY, these sessions, presented by dedicated, passionate researchers focused on the wealth of new options that are becoming available to patients, the on-going work of sorting out sequencing and combinatorial usage, and the importance of patients seeking care from oncologists and urologists with specific, up to date knowledge of the state of the science in renal cell carcinoma. One size definitely does not fit all.
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