Toggle Menu

Press Room

Notes from the Eigth International Kidney Cancer Symposium

01/25/2010

We are grateful to patient advocate Katherine Phillion for sharing her notes from our fall kidney cancer meeting. 

Eigth International Kidney Cancer Symposium
September 2009
 
 
Management of Small Renal Masses and Localized Renal Carcinoma
Case Presentation and Background
Robert G. Uzzo, M.D., FACS
There are a lot of options available to manage small (<4cm) tumors that are limited to the kidney
-       cut it out via surgery
-       ablate it via freezing (cryo) or heating (RFA)
-       watch it
 
In selecting an approach, the surgeon’s goal is to maximize disease free survival and minimize negative side effects…Selection is often based on the surgeon’s training/comfort level with each option and his/her evaluation of the trade-offs associated with each approach. Relative to an open partial nephrectomy (Nx), there is   
 - increased risk of chronic kidney disease w/ a radical Nx (removal of entire kidney)
 - increased complication rate w/ laparoscopic Nx (minimally invasive or small incision)
 - no long term efficacy data on thermal ablation…and ability to salvage (patient advocate perspective: if it doesn’t work, next step is not clear as scarring from cryo/RFA makes subsequent surgery more difficult)
 - increased patient anxiety w/ surveillance and no biomarkers or predictors of growth
 
To help make option selection more objective, Fox Chase Cancer Center has documented a surgeon friendly system which can be found at www.nephrometry.com
 
AUA small renal mass guidelines:
-       cancer control is top priority
-       preservation of renal function is high priority (take out part vs. all of kidney when possible)
-       minimally invasive surgery is encouraged when appropriate
 

 
Major Urologic Complication
Local recurrence-free survival
OPNx
6.3%
97.4%
LPNx
9.0%
98.4%
ORNx
1.3%
98.1%
LRNx
3.4%
99.2%
 
 
 
Cryo     
4.9%
90.6%
RFA
6.0%
87.0%

 
O = Open
L = Laparascopic
* Ablation date is early w/ RFA and cryo treating smaller tumors with shorter follow-up
 
 
Chronic Kidney Disease Implications in Kidney Tumor Surgery
Paul Russo, M.D., FACS
Chronic kidney disease (CKD) is a progressive loss of kidney function over a period of months/years. CKD is
-       increasing in prevalence due to increasing obesity, high blood pressure and diabetes. 
-       Bad as it is an independent risk factor for cardiovascular disease, hospitalization and death. 
Surgeons are questioning whether over-use of radical nephrectomy is negatively impacting survival by causing CKD. Preserving renal function is important so partial nephrectomies should be considered for small renal masses as this approach is thought to be protective of kidney function.
 
Thermal Ablation
Jeffrey A. Cadeddu, M.D
In management of small renal masses, for the right patient partial nephrectomy is a good approach as it is nephron-sparing and provides excellent local cancer control. It is important to recognize that with a partial nephrectomy comes complications and recovery. Also, pre-surgical biopsies are important to make sure tumor is not benign…you don’t want to do an unnecessary surgery on a benign tumor.
 
An alternative to partial nephrectomy in the management of small renal masses is thermal ablation.
Ablation refers to a local method that destroys the tumor without removing it. Cryoablation is a freezing technique and Radio Frequency Ablation is a heating technique. Advantages of ablation relative to a partial nephrectomy are that ablation has less complications and can be done on an outpatient basis or w/ 1 day hospital stay. Disadvantages are less competitive/no long tem efficacy data on ablation and ability to salvage. Initial data suggests that RFA is similar to partial nephrectomy as a preserver of renal function. Radiographic follow-up is required. Dr. Cadeddu suggests annual imaging after the 1st year vs. images every 6 months for active surveillance. Another advantage of ablation relative to active surveillance is that patient drop out rate from the surveillance program can be as high as 40%. It is important to have an experienced doctor perform the ablation procedure. 
 
 
Active Surveillance
Michael A.S. Jewett, M.D., FRCSC, FACS
The most common presentation of renal cell carcinoma is the small renal mass (< 4 cm) which is usually detected incidentally and without metastatic disease.
 
Not all renal masses are kidney cancer.  Biopsy is recommended to determine if tumor is benign. Twenty percent of tumors < 4 cm are benign. Belief is that the smaller the mass, the less the metastatic rate and the greater the survival. Experience is showing that small tumors initially grow at a negligible rate even if biopsy proves the tumor is renal cell carcinoma.
 
There is a growing body of Canadian and U.S. data that suggests active surveillance of the small renal mass with delayed treatment for progression appears to be a reasonable initial management option in selected patients (older or infirm)…this approach is not yet recommended for young and fit. 
 
Active surveillance requires regular imaging and careful measurement of tumor size/volume. The optimal surveillance protocol is unknown. The progression trigger(s) for metastatic disease is not yet defined.
In Canadian and U.S. studies there is a notable 1.5-2% risk of progression to metastatic disease even though the renal mass is still of small size (~2.5cm) suggesting that an additional prognostic factor besides tumor size needs to be identified and monitored.
 
 
Management of Locally Advanced Kidney Cancer
Case Presentation and Background
Allan Pantuck, M.D., FACS
The TMN staging system is a common language/basis to communicate the extent of disease and assists in evaluating a treatment path. TMN stage T1 and T2 tumors are limited to the kidney. T3 and T4 tumors are locally advanced if there is lymph node disease in a single region and no distant mets.
          T1 – tumor is limited to the kidney, < 4cm (1a), 4-7 cm (1b)
          T2 – tumor is limited to the kidney but > 7 cm
          T3a – tumor directly invades adrenal gland or fat
          T3b – tumor extends into the renal vein or vena cava below the diaphragm
          T3c – tumor extends into the vena cava above diaphragm or invades the vena cava wall
          T4 – tumor invades beyond Gerota’s facia (the layer of tissue encapsulating the kidney)
 
          N0 – no regional lymph node mets
          N1 – mets in a single regional lymph node
          N2 – mets in more than one regional lymph node
 
          M0 – no distant mets
          M1 – distant mets
Risk of disease progression/recurrence and consequently decreased survival increases with increasing TMN stage and increases with increasing tumor grade (runs from 0 to 4). For small renal masses, median survival for grade 4 tumors is only 11 months. Another factor known as the ECOG score which is a measure of a patient’s general well-being is also important in considering the risk of disease progression/recurrence. An ECOG score of 0 denotes perfect health and 5 denotes death. Directionally, patients with higher ECOG scores do not do as well as patients with lower ECOG scores.
 
 
Lymph Node Dissection
Michael L. Blute, M.D.
For patients without distant mets, 5/10 yr survival is 48/32%. Patients with distant mets have a 5 yr survival of 7%
 
Whether to cut out lymph nodes during a nephrectomy is controversial. The CT scan sensitivity for nodes > 1 cm is 95%...only about 42% of these nodes are disease positive.
 PRO: Lymph node dissection (LND) offers
-       improved staging and prognostication (a doctor's prediction about a disease path)
-       improved survival in patients with confirmed advanced kidney cancer whose nodes are positive but do not have distant mets
CON: Lack of proven survival benefit studies
 
In the overall management of kidney cancer, he recommends:
T 1a/1b: No LND
T2-4, N0, M0: LND based on pathological features @ surgery if possible/Mayo/MSK pre-op nomogram
cT2-4, N+, M0: LND is standard of care
cTany, N+/-, M+: cytoreductive surgery then LND
 
 
Neoadjuvant Therapy for Locall Advanced Disease
Eric Jonasch, M.D. 
Neoadjuvant therapy refers to systemic drug treatment given to people with cancer prior to surgery. For local control of the primary tumor, an optimal neoadjuvant therapy:
1. Is safe
2. Decreases size of primary tumor
3. Results in tumor downstaging to potentially permit resection of a technically difficult to remove tumor or allow for partial nephrectomy (ie retraction of IVC thrombus, or decreased invasion into adjacent organs).
 
Local control of primary tumor: summary table of neoadjuvant trials results -

 
 Study
Patient population
# of Pts
 
Safe?
Primary Tumor
Shrinks
Amount of
Shrinkage
Down-staging?
Sorafenib
(UNC/ prospective)
≥T2 RCC; sorafenib 400 mg BID x
4–8 wks prior to Nx
30
Yes
64%
11% 
(range, 0–40%)
Yes
Bevacizumab 
(+/- erlotinib)
(MDACC/prospective)
RCC Pts w/mets prior to Nx; treatment x 8 wks
50
Yes
51%
***
No
Sunitinib (CCF/prospective)
‘Unresectable’ RCC
18
Yes
72%
19% 
(range, 1-64%)
Yes
Sunitinib
(Netherlands/retrospective)
M+ pts w/ primary
17
Yes
59%
12% 
(range, 2-33%)
 
Sunitinib (CCF/retrospective)
‘Unresectable’ RCC
19
Yes
42%
24%
 (range, 2-46%)
 

 
Did current neoadjuvant therapy:
1. Decrease size of primary mass? YES
2. Convert complete to partial nephrectomy? IN SOME CASES
3. Result in retraction of IVC thrombus, or decreased invasion into adjacent organs? NOT TOO OFTEN.
4. Change biology of primary tumor from invasive to noninvasive. UNPROVEN
However, we need better drugs.
 
Conclusions on Optimal Systemic Control For High Risk Patients:
  - Anti-angiogenic agents are capable of reducing primary tumors, but not consistently.
 - There is no evidence that anti-angiogenic agents are anti-metastatic
  - Monitoring tools/markers need to be developed that can measure efficacy of anti-metastatic drugs
 
As a patient advocate I point out that in the summary table of neoadjuvant trials results for local control: There is a learning curve to use these drugs safely and effectively. The current neoadjuvant therapy approaches were safe in the hands of experienced clinicians…an example is that some patients had incomplete wound healing and had to have their treatment approach altered “on the run”.”
******************************************************************************************
******************************************************************************************
 
Emerging Applications of VEGF and mTOR-Targeted Therapy
Case Presentation and Background
Brian I. Rini, M.D.
When kidney cancer spreads in the body, it is called metastatic disease.  Metastatic disease is the focus of presentations in this session. Dr. Rini presented a stage IV kidney cancer case and discussed initial treatment and follow-up options…subsequent presentations in this session of the symposium were designed to test/influence how the doctor might treat a similar patient in the future.
 
 
Standards of Care and Current Single-Agent Clinical Trials
Robert A. Figlin, M.D.
To treat kidney cancer multiple agents are available:

Agent
 
Route of administration
Type of Agent
 
Sutent®
sunitinib malate
oral
TKI
 
Nexavar®
sorafenib tosylate
oral
TKI
 
Torisel®
temsirolimus
infusion
mTOR inhibitor
 
Afinitor®
everolimus
oral
mTOR inhibitor
 
Avastin®
Bevacizumab
infusion
Monoclonal antibody
Figlin bias is Bev + IFN if go w/ this approach
Votrient®
pazopanib
oral
TKI
6th approved for kidney cancer since 2005

 
Dr. Figlin said
 - they are starting to understand agents better and how to use them to treat the patient in front of them  
 - patterns of relapse are different than a decade ago and
 - sequential targeted therapy is the standard of care for kidney cancer. 
 
Current treatment strategy is to select a first line therapy based on a patient’s prognosis and select a 2nd line therapy based on prior therapy.
  • Sunitinib superior to IFN-α in first-line setting (PFS, OS benefit)
  • Sorafenib superior to placebo in second-line setting (PFS benefit)
  • Bevacizumab + IFN-α superior to IFN-α alone
  • Temsirolimus associated with survival improvements over IFN-α, particularly in poor-risk patients
  • Afinitor® (everolimus) beneficial after first-line sunitinib/sorafenib
Nurses are important in managing proactively side effects w/ the patients.
 
New Standards for Clear Cell Kidney Cancer Therapy:
.
Limitations of Single Agent Targeted Therapy for metastatic kidney cancer
  • Few patients attain complete responses
  • Continued treatment appears required
  • Resistance usually develops in 6-12 months
  • Survival benefit with targeted agents:
    • Sunitinib – 4.6-month survival benefit vs IFN-α1
    • Sorafenib, bevacizumab, everolimus – No overall survival benefit demonstrated.  As a patient I point out that survival benefit is hard to prove w/ some of the cross-over trial designs that allow the patient w/ progressive disease to receive the investigational drug however I am glad to see the patients get the drug.
    • Temsirolimus – 3.5-month overall survival benefit vs IFN-α in poor-prognosis patients
 
I note that this information may be disappointing to you however please recognize that I am a 15 year survivor of stage IV kidney cancer…and we have 6 more treatment options than we had in 2005. New developments continue and the doctors continue to evaluate different combinations and sequences. I am reminded that more than ever, it is most important for some one with kidney cancer to get to a Center of Excellence (COE) for treating kidney cancer. The KCA can refer you to one. If not possible to have all treatment at a COE, make sure your home town Doc consults with a COE. 
 
Strategies for overcoming RCC challenges
  • Combination therapy – have additional challenges of inadequate activity and/or enhanced toxicity
  • Sequential therapy – Several new agents showing activity
 
Investigational Targeted Agents in the clinical trial pipeline:

Agent
Efficacy
Route Administered
Where in pipeline?
 
AV951
PR 20%; SD 72%
Median PFS not
reached at 13 mos
oral
Phase II
Bhargava P et al. 2009 ASCO Genitourinary Cancers Symposium. A5032.
Axitinib
PR 21%; SD 34%
Median PFS 7.4 mos
oral
Phase II
Rini BI et al. ASCO 2007. A5032.
Pazopanib
 
Median PFS:
All patients
No prior therapy
Cytokine-treated
 
ORR:
All patients
No prior therapy
Cytokine-treated
 
Median OS*
Pazopanib  Placebo
 (n=290)     (n=145)
 
   9.2 mos     4.2 mos
 11.1 mos    2.8 mos
  7.4 mos     4.2 mos
 
 
30%         3%
32%         4%
29%         3%
 
21.1 mos   18.7 mos
oral
Phase III
Sternberg CN et al. ASCO 2009. A5021.
Global, randomized, double-blinded 
 
 
 
 
 
 
 
 
 
* 48% of placebo-treated patients switched to pazopanib upon progression. Survival benefit is hard to prove w/ cross-over trial design that allows the patient w/ PD to receive the investigational drug.

PR = partial response, SD = stable disease, PD = progressive disease, PFS = progression free survival, ORR = overall response rate, OS = overall survival
 
 
Intermittent Therapy with Tyrosinekinase Inhibitors
Viktor Grunwald, M.D.
TKI’s or tyrosine kinase inhibitors interfere with the reproduction of cancer cells by blocking one or more growth pathways. Different drugs target different pathways. Current approach is sequential targeted therapy or continuous administration of drugs until either toxicity or PD prevail. 
Based on success in CML patients, in kidney cancer doctors are trying an intermittent therapy approach to reduce toxicity and preserve the anti-tumor effect of the drugs. They are looking for the right marker to monitor/use w/ each drug to guide drug administration as dose/administration schedule will be key to success. Dr. Grunwald believes that drug wash out can be safely applied w/in a window of several weeks. As a patient I was glad to see that he backed this belief by presenting data that suggests that TKI wash out prior to a second therapy is associated with a better response…this data will make my next wash out less stressful.
 

Wash Out
(days)
# Patients
Overall Response Rate
>30
25
6 (24%)
<30
25
0 ( 0%)

 
1st line treatment: Bevacizumab or Sorafenib
2nd line treatment: Sunitinib
Dr.Grunwald also believes the best continuous vs.intermittent drug dosing approach will be specific to each drug.
 
 
Therapy Re-Challenge
Thomas E. Hutson, D.O., PharmD.
Dr. Hustson presented the concept of rechallenging a patient to the drug that had given him the most benefit. Idea came out of dilemma of what to do (phase I trial, treatment or hospice) after patient had done all of the available therapies and still had a good performance status. The following rechallenge experience is w/ Sunitinib in a 4th, 5th or 6th line setting.
 
Several centers pooled their data to find a group of 23 patients who had Sunitinib as a 1st, 2nd or 3rd therapy, went on to receive a variety of other treatments and subsequently were rechallenged w/ Sunitinib. Results were as follows:
  - Median PFS for the group was 7 months.
 - Patients who had an initial response to Sunitinib were likely to have a PR or SD w/ rechallenge. 
 - Best response: PR / SD / PD was 5 (22%) / 17 (75%) / 1 (4%)    
 - For the majority of the patients, PFS with initial Sunitinib was > PFS with rechallenge.
                                                    PFS (months)
                           Initial                         13.7
                           Rechallenge               7.2
 
 - Patients w/ > 6 months between initial Sunitinib and rechallenge had greatest response rate and PFS. 
 
He points out that these results were in a highly select group of patients and that further studies are required. He posed the question “Does it take a certain amount of time to reset the resistance pathways so that people can respond again?” It is possible that a rechallenge benefit may not be limited to Sunitinib …and that what is important is a rechallenge w/ the drug that had given the patient the most benefit.
 
(PR = partial response, SD = stable disease, PD = progressive disease, PFS = progression free survival, ORR = overall response rate, OS = overall survival)
 
Alternative Dosing Schemas of VEGF and mTOR therapy in metastatic RCC
Toni K. Choueiri, M.D., M.S.  
Dr. Choueiri presented current FDA-approved schedules for kidney cancer drugs:
 - Sunitinib: 50 mg PO QD (by mouth once a day), 4 wks on / 2 wks off
 - Sorafenib: 400 mg PO BID (by mouth twice daily)
 - Bevacizumab: 10 mg/kg IV (intravenous) q2weeks
 - Temsirolimus: 25 mg IV weekly
 - Everolimus: 10 mg PO QD (by mouth once a day)
 
Available information on alternative dosing schedules:
Sunitinib: NO difference in taking drug in AM or PM. There are studies in progress to determine whether 4/2 vs. continuous dosing schedule is better. He underscores the importance of getting to/staying at FDA recommended dosing as patients w/ the highest Sunitinib exposure have longer time to disease progression and greater overall survival. Challenge is management of the side effects at that dosing.
 
Sorafenib: Data from a Dr. Robert Amato study suggests patient benefit from rapid dose escalation to 800 mg… Prospective trials comparing the standard dose and the dose escalation strategy are required          

Dose escalation upon progression
(600 mg PO BID, by George et al ASCO 2008)
Rapid dose escalation
(600 mg bid D 29-56; 800 mg bid D 57+, by Amato et al ASCO 2007)
• 14 patients
• PFS: 3.4 months
• ORR: 7%
• 71% pts dose escalated
• 46 patients
• PFS: 8.4 months
• ORR: 55%!
• 93% pts dose escalated

 
mTOR inhibitor: it is not known if daily dosing is better. Current mTORs target mTORC1…He advocates potentially using current mTOR drugs in combination w/ future drugs that target mTORC2.
 
 
Combination Therapy: Exisiting Data and Ongoing Clinical Trials
Keith Flaherty, M.D.
Dr. Flaherty focused his talk on clear cell RCC and targeted agents (not cytokines). Goal of combining agents is to find complete responses and improve overall survival. However, have to be careful in trial designs as synergy can play out in toxicity as well as efficacy. He reviewed early combination trials and several in progress. Toxicity has been a challenge…in combination, have not been able to get patients to full therapeutic doses of the individual drugs. Favorable results have been seen in Sorafenib w/ Bevacizumab: 52% response (48 patients: 25PR, 18SD, 4PD, 41 w/ tumor decrease), 14 month median PFS.  The hope is that newer more potent drugs may be able to achieve these results individually. Not all combinations are equally promising…Bevacizumab w/ erlotinib is an example of one that did not pan out.
 
 
Abstract Presentation: Phase II trial of continuous once-daily dosing of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma (mRCC)
Sun Y. Rha, M.D
120 patients were enrolled in this study to evaluate one year of continuous once daily dosing of 37.5 mg of sunitinib. Only 35% were able to stay on the continuous dosing for the planned one year of treatment. 65% discontinued the treatment due to side effects. 116 were evaluable for tumor response…Results should be available soon. 
 
 
Prediction of Response and Toxicity in Metastatic RCC
Overview of Prognostic / Predictive Markers in Metastatic RCC
Robert J. Motzer, M.D.
Prognosis is a medical term to describe the likely outcome of a disease. Treatment for kidney cancer has changed over the last decade however the same factors that predict the aggressiveness of kidney cancer are valid for cytokine, chemo and targeted therapy. These factors include:
 - Performance status
 - Whether a nephrectomy has been done
 - Extent/Sites of metastatic disease
 - Various Biochemical parameters
No factor is an independent predictor of survival all of the time.
 
Prognostic factors not only are a tool for predicting patient outcome but they can also aid in individualizing patient treatment. Dr. Escudier looked at the Bevacizumab data and interpreted that patients who benefit most are the favorable and intermediate risk group and not so much the poor risk group. 
 
For Temsirolimus, eligibility into the clinical trials was poor prognosis factors to determine if poor risk patients would benefit from the treatment…as a result we know that poor risk patients do benefit from this therapy.  Now Temsirolimus is the standard of care for poor risk patients.
 
Doctors are also looking for molecular factors that may predict outcome. The best example is CAIX for IL-2 which was developed by Dr. Atkins’ group. 
 
Dr. Motzer said, “The goal is to identify molecular features that predict the likelihood that a patient will respond to a therapy based on tumor biology. Then integrate the molecular predictive info with the clinical data to drive new drug development, clinical trials and therapy.”
NeonCRM by Neon One