IKCS Summary

Roxanne Payne, FNP, AOCNP

Watch videos of this symposium

Clinical Epidemiology of the Small Renal Mass:  Contemporary Trends and Implications for Patients—Dr. David C. Miller

The following case study was utilized to frame this discussion: 

A patient with a 4 cm mass without evidence of metastasis and with no other symptoms presents for treatment options.  The audience vote was for partial nephrectomy.

A small renal mass is defined as:

• A contrast enhancing mass (CT Scan) approximately 4 cm or less
• 50-60% of all renal tumors are defined as SRM’s
• Approximately 80% are malignant.

The incidence of RCC has risen in the past 2 decades with the median age at diagnosis 60-65 years.  Of note, the incidence of younger age at diagnosis may be increasing, a change in the past few years.  Most patients present with localized tumors (about 60%).  Also noted, mortality for patients with localized tumors may be increasing.

Hypertension and diabetes are the top comorbid conditions associated with kidney cancer (SEER data).

The discussion of epidemiology was centered on determining ways of decreasing morbidity and mortality in patients with SRMs. 

Several options are now available to patients including:

• Nephron sparing excision (partial nephrectomy)
• Nephron-sparing thermal ablation (Cryoablation/radiofrequency ablation)
• Minimally-invasive surgery (laparoscopy, robotics, percutaneous)
• Active surveillance

Of available options open radical nephrectomy is curative in most cases, widely available, safe and cost-effective.  Now focus on preservation of non-malignant kidney tissue if possible and therefore an increase in the use of partial nephrectomy.  More recent surgical advance such as laparoscopic technique reduce incision-related pain and morbidity, shorter hospital stays and an easier more rapid convalescence in the post operative period.   Tan and colleagues in a population level comparison of the effectiveness of laparoscopic vs. open nephrectomy, found having a laparoscopic procedure reduced the likelihood of intensive care admission and resulted in a decreased length of stay, although re-admission rates were similar (published in Cancer 2011).  Although the patients who underwent laparoscopic procedures were less likely to require ICU level care, they also had higher rates of in hospital mortality (more likely to die acutely after surgery).  This is thought possibly to be due to challenges in recognizing or treating post operative complications, potentially related to experience level of the surgeon or hospital with the procedure.

Final questions from this presentation section: 

• Is an uncomplicated radical nephrectomy better than a partial nephrectomy with significant post operative complication? 
• Is there a survival advantage with partial nephrectomy vs. radical nephrectomy?

Renal Mass Ablation

Dr. Thomas Atwell

Partial or radical nephrectomy remains the standard of care for renal masses.  For patients with significant co morbidities consideration is given to ablation—either cryo or radiofrequency ablation.  This may be due to the patient’s other comorbid conditions or patient preference.

Indications for ablation:

Size is a relative consideration.  Initially, smaller tumors were treated with these techniques. 

Location:  for tumors close to the ureter, the use of stent, irrigation allows for better identification of the ureter.  Also consider proximity to the bowel and adrenals (requires BP monitoring and possibly alpha blockade).

Radiofrequency Ablation:

Strengths:

• Easy to use
• Fast (8-10 minutes)
• Safe

Weaknesses:

• Not for larger tumors
• Thermal sink effects
• Inability to monitor

Clinical Outcomes:

• Control rates are approximately 90-97%.
• Smaller tumors can be successfully controlled.
• <3cm – 39 months of follow up
• >3 cm 60% success
• Central tumors are harder to treat—peripheral tumors have a higher chance of successful ablation.

Complications (~5%):

• Nerve injury (usually resolves in about 6 months)
• Bleeding (rare—1%)
• Ureteral stricture (1-2%)
• Abscess
• Urinoma
• Pneumothorax
• Bowel injury

Cryoablation

Strengths: 

• Effective for large tumors, centrally located masses
• Durable:  approximately 88%-98%
• Cryoablation of large central tumors >92% local control compared with 60-81% with RFA

Weaknesses

• Bleeding
• Cumbersome to use

Complications ~6%

• Bleeding (3%):  size and number of probes, central tumors increase risk.
• Hematuria occurs in 2-3%
• Pulmonary embolus (1%)
• Nerve injury (1%)
• Other medical event (1%)
• Infection/abscess
• Seeding
• Bowel injury
• Pneumothorax

Expanding horizon:  there may be cryo-immunologic response:  cell disruption/death as a result of cryo, potentially provides a unique tumor/antigen environment.  Additionally, now defining long-term efficacy, consideration of ablation of “benign” tumors.  Other technologies:  microwave, LITT, FUS, IRE.

Active Surveillance of the Incidental SRM

Dr. Robert Uzzo

A case study was utilized as a framework for this discussion:  a 65 year old man with a 1 cm renal mass (first noted 3 years prior).  The medical history is significant for hypertension, coronary artery disease and MI, also moderate COPD.  Labs are significant for creatinine 1.5 mg/dl. 

As in many cases, we do not know the length of time it has been present, how fast it has grown, histology or grade or its biologic potential. 

What we can predict about SRMs: 

• Pathology:  70-75% malignant tumor
• 15-20% it is a high grade tumor based on nephrometry
• Cure rate:  97-99% at 12 years based on preoperative data
• Life expectancy:
  • 10-12 years based on NCCN senior oncology tool
  • 20% alive at 10 years
• Competing risks:  6 times more likely to die from causes other than RCC in 5 years.

Pathology of localized SRMs is predominantly low risk (not always). 

Most metastatic tumors started out as a larger renal mass.  We may be able to predict whether the cancer will be aggressive. Utilizing nomograms, www.cancernomograms.com, it may be possible to make a case for active surveillance versus surgery.   This takes into account the patient’s age, gender, history of smoking, and size of the mass.  Points are assigned and totaled to give a probability of aggressiveness.

It is also known that the pathology of localized SRM’s are predominantly “low risk”, although not always.  Size has been shown to predict histology and grade:  in an analysis of 18,818 cases (SEER analysis) for tumors <4cm 86% were low grade (N=7729), and 14% high grade (N=1250). 

Imaging shows growth rates of localized SRM are slow.  In an analysis of 880 patients, the median growth rate in cm/year was 0.08-0.58 cm.  The overall mean follow up was 34 months.  35% of the lesions had net zero growth on imaging:  none progressed.  In the same study, primary tumor size and progression to metastatic RCC was also analyzed. 

Decisions regarding active treatment versus surveillance are quite subjective.  It was proposed the following, along with operative risks, should be calculated:

• Performance status
• Co-morbidity index
• Competing risks of death
• Complications
• eGFR and risk of chronic kidney disease
• complexity of partial nephrectomy
  • nephrometry score

In a small subset of patients (n=18) the median time to progression was 40 months.  In another subset of 151 patients, the median tumor size at intervention was 2.3 cm with a mean linear growth rate of 0.44 cm/yr.  The minimum delay was 12 months.  None progressed to metastatic disease.  Of the entire 880 only 3 developed metastatic RCC within 3 years of active surveillance. 

In a study by Haramis, et al, 44 patients with 51 tumors underwent active surveillance.  The median age was 72 (55-92), 73% CCI >2 (Charlson comorbidity index).  Median follow up was 77 months (60-137) with median growth rate 0.15 cm/year.  4.5% required delayed intervention.  There were NO metastases or cancer related deaths.

Overall a strong case was made for active surveillance utilizing tools available to predict which patients would be most appropriate.

Nephron Sparing Surgery aka Partial Nephrectomy

Paul Russo, MD

Over the past 20+ years there have been many advances in imaging, increasing numbers of tests ordered for nonspecific abdominal or musculoskeletal complaints or during unrelated cancer care and surgical oncology began to change approach to organ and limb preservation.  We have now moved to an era of elective partial nephrectomy (PN) from essential PN. 

• Essential PN:  reserved for patients who had a tumor in a solitary kidney, bilateral renal tumors or had renal insufficiency. 
• Elective PN is increasingly done in patients with renal tumor and normal contra lateral kidney.
• Extended PN:  for a case in which tumor is not controlled with other measures such as ablation. 

Fundamental supporting PN:  about 20% of resected renal masses are benign and 25% have limited metastatic potential.  54% are conventional clear cell (account for 90% of metastasis).  It is also noted up to 25% of patients have preexisting chronic kidney disease (CKD).  PN preserves renal function and prevents or delays the development of CKD and other morbidity and mortality such as from cardiovascular disease. 

Complications of PN: occurs in up to 9% of patients—more commonly in those with solitary kidneys and longer operating time.  Complications reported in 2 studies included urinary fistula in 4.4% (52\1118), 69% of which resolved without any additional intervention.  AV fistula occurred in 15/1461(1.02%).  Of these 14 were treated successfully with angioembolization and 1 required emergency nephrectomy.

Dr. Russo reports that PN is attempted in all patients with <7cm tumors.  Safety is of greater importance than technique (laparoscopic versus open).  GFR testing in all patients recommended. 

Ischemia Time

R. Houston Thompson, MD

Several published reports were reviewed on ischemia times (cold and warm) during nephron sparing surgery/partial nephrectomy.  One in particular was reviewed extensively and was recently published in the Journal of Urology Feb. 2011:  Comparison of Cold and Warm Ischemia During Partial Nephrectomy in 660 Solitary Kidneys Reveals Predominant Role of Non-modifiable Factors in Determining Ultimate Renal Function (Lane, B. R., Russo, P., Uzzo, R.G., Hernandez, A.V., Boorjian, S.A., Thompson, R.H., et al)

• All patients had a solitary kidney.  Those with warm or cold ischemia were nearly evenly distributed.
• Age, tumor size, preoperative GFR and percent kidney preserved predicted GFR. 

Conclusions: 

• Ideal ischemia time is 20-25 minutes or less improves short and long term renal function.  >25 minutes carried 5 year risk of new onset stage 4 CKD
• No differences on GFR for cold vs. warm ischemia times
• Preoperative GFR and the percent of kidney preserved was a better predictor of post op GFR. 
• No ischemia preserves renal function better than warm.
• Longer cold ischemia times were equivalent to shorter warm ischemia times.
• Quality and quantity of the remaining kidney is associated with ultimate renal function.

Robotics in RCC Surgery

Gennady Bratslavsky, MD

The opening question for this presentation was:  is there a future for robotic PN?

• At Society of Urologic Oncology (SUO) 2007 meeting there were no abstracts presented on robotic PN.
• In 2009 there were 9 from 6 different institutions.
• Now a search in pubmed will yield a more than two hundred abstracts

The use of robotics in RCC includes management of SRM, T1b disease, high nephrometry score management, management of multifocal and recurrent RCC as well as in locally advanced RCC. 

In a comparison of treatment versus cost active surveillance carries a risk of progression, anxiety on behalf of the patient and frequent imaging to monitor status.  Ablation procedures are carried out with less pain and scarring, less anxiety and functional loss, but imaging interpretation can be difficult and patients may progress despite treatment.  Open or lap radical nephrectomy  is complicated by pain, scar and functional renal loss as well as an increase in mortality.  Open/lap/robotic partial nephrectomy results in less functional loss, but possibly an INCREASE in mortality.

A guideline for management of clinical stage 1 RCC:

Benefits of da Vinci nephrectomy and PN:

• Less pain
• Less blood loss and fewer transfusions
• Less risk of infection
• Less scarring
• Shorter hospital stay and recovery time
• Increased potential to preserve the kidney
• Better clinical outcomes in many cases.

Data analysis of > 100 procedures using robotic partial nephrectomy versus laparoscopic PN for RCC reveals robotic PN had significantly shorter ischemic times and a shorter hospitalization.

Robotic surgery is likely equivalent to open or laparoscopic nephrectomy.  Grade 3 and 4 complications occur in up to 23% of patients.  Conversion to open partial nephrectomy occurs frequently.  Renal function is well preserved.  Additional uses of robotics in RCC include patients with solitary kidney (just a couple of reports), locally advanced disease; larger tumors—consideration if need RPLND.

A couple of points from the conclusion

Active surveillance:  There is not enough data in young patients or in patients with a life expectancy >20 years to recommend active it in those populations.

How often to biopsy:  gives greater understanding of tumor biology.  Can consider results in conjunction with other co-morbidities as well as the functional vs. cancer risk.

Prognostic factors for mRCC:  Clinical and Molecular Features

Daniel Heng, MD, MPH, FRCPC

Molecular challenges include defining molecular biomarkers/outcomes.

Prognostic factors include:

• Patient factors:  performance status, symptoms

• Tumor burden:
• Prior nephrectomy
• Sites of metastasis
• Bone mets
• Elevated LDH
• Anemia
• Calcium
• Sodium

 

• Proinflammatory Markers

• IL6
• ESR
• Neutrophilia
• Thrombocytosis
• C reactive protein

 

• Treatment related factors:

• Prior therapy
• Prior radiotherapy
• Disease-free interval
• Diagnosis to treatment interval

MSKCC criteria is the most widely used to predict survival in kidney cancer.  This uses performance status (Karnofsky), time from diagnosis to treatment (<12 months), elevated LDH, anemia and elevated calcium levels are along with other variables.  There are favorable, intermediate and poor risk categories.  No or zero factors = favorable risk, one or 2 factors= intermediate and more than 2 = poor risk.

In the era of immunotherapy and targeted therapies additional criteria were developed:  IKCWG prognostic criteria for survival—9 variables are analyzed and patients can be classified into 3 groups including favorable, intermediate and poor prognosis. 

Evidence of selected molecular biomarkers (VHL alterations, HIF-1α, VEGF-A, etc) in RCC was reviewed.  There is much conflicting evidence regarding the role of these as prognostic factors or as predictors of response in targeted therapies, or the role is yet to be defined.  All require external validation. 

Prognosis on the genetic level: 

The AXIS study was reviewed. Treatment refractory mRCC patients were randomized to receive either axitinib or sorafenib.  Genotyping analysis showed a potential association between VEGF-A SNPs (single nucleotide polymorphisms) and progression free survival.  This appeared to be driven more by axitinib than sorafenib.  There were low patient numbers with SNP analysis available, but this is an area of great interest warranting further study.  In pazopanib studies none of the SNPs were associated with overall survival in patients who did not receive pazopanib.  Limitation:  There were small sample sizes.

Overall SNPs need external validation and larger patient numbers.  Current studies predominantly include Caucasian population—protocols need to include patients of other races for stratification.  Eventual goal would be to use as predictive markers in drug selection or to prognosticate overall survival.

Predictive Markers:

Hypertension after the 1^st cycle of sunitinib is associated with better overall response rate, PFS and overall survival—this is helpful once treatment is initiated, but does not help guide choice of therapy.

Clear Cell RCC:  Update on TCGA

W. Kimryn Rathmell, MD

Dr. Rathmell updated TCGA progress for clear cell RCC (ccRCC).  There has been accrual of >900 samples.  Accrual is now closed.  327 included in data freeze.  There are 4 sub analyses:  211 core samples (RNAseq, CNV, Seq, methylation), 81 extended data sets, 20 w/ history prior treatment to be analyzed separately and 15 with potential histological classification error.

Platforms for integrated analysis include:

• Gene expression:  RNA seq
• RNA splicing
• microRNA
• copy number analysis
• SNP analysis
• Whole exome sequencing (whole genome on 20 selected tumors
• DNA methylation
• proteomic s

190 key genes.  Most with mutation of VHL

Copy number variation:  frequent loss of chromosome 3, amplification chromosome 5.

Conclusions

• VHL/PBRM1 mutations confirmed
• 3^rd subtype identified and under review but appears to be mis-classified tumors.  Shows value of molecular methods rather than new mechanistic insights.
• Integration with survival outcome—suggests molecular detailing can be prognostic
• Full integrative analysis in process
• Preliminary data can be found at http://tcga-data.nci.hih.gov/tcga/

FoxO Transcription Factors in mTORC1- Activated Renal Tumorigenesis:  Implications for the RCC Treatment

Boyi Gan, MD Anderson Cancer Center

• FoxO Family Transcription Factors:  mammals possess FoxO1, FoxO3, FoxO4 and FoxO6.
  • FoxO1/3/4 are regulated by PI3K – AKT signaling.
    • Inhibits cell survival and proliferation.  Promotes apoptosis and cell cycle arrest in mammalian cell culture systems, putative tumor suppressor role. 
    • In mouse models somatic deletion of TSC1 leads to the development of polycystic kidney and renal tumor. 
    • Dual inactivation of FoxO and TSC1 dramatically drives renal tumor progression. 
    • FoxOs are extinguished in the majority of human renal tumor samples. 
    • Broad somatic deletion of all 3 FoxOs was shown to engender a cancer-prone condition dominated by hemangiomas and lymphomas.
• Myc signaling is the key downstream effector of FoxOs in the regulation of renal tumorigenesis.
• A combination therapy to target both mTOR and FoxO is suggested in human RCC. 
• mTORC1:  hyperactivation is observed in the majority of human RCCs.  mTORC1 inhibitors showed clinical benefit in RCC clinical trials. 
• FoxOs serve as a critical checkpoint to constrain mTIORC1-mediated renal tumorigenesis and novel tumor suppressors in renal cancer.

Novel RCC Mutations

Astrid van der Veldt, MD

Sunitinib was approved in 2006 for treatment of advanced RCC and is the most widely prescribed drug.  About 35% of patients do not benefit from sunitinib.  Pretreatment markers to identify mRCC patients who would have a favorable outcome to sunitinib would be of great value.  SNPs may be useful for personalized treatment planning in mRCC patients.

Dr. Van der Veldt presented the research conducted on sunitinib.  The objectives were to identify genetic polymorphisms that are associated with prolonged PFS and/or OS in mRCC patients treated with sunitinib, sunitinib-induced toxicities and sunitinib-induced hypertension.

Patients treated with sunitinib were recruited from 6 Dutch medical centers.  136 sunitinib treated mRCC patients with clear cell histology were included in the efficacy analysis; 219 sunitinib treated patients w/ various malignancies were included in toxicity analysis; 291 sunitinib treated patients w/ various malignancies were in hypertension analysis.  Germline DNA was isolated from blood samples.  37 polymorphism im 15 candidate genes were analyzed.  PFS and OS were determined for efficacy analysis.  Toxicities were graded w/ CTCAE v. 3.0.

Favorable genetic profile was associated with improved outcome in multivariate analysis:  carriers of this profile had at least

• An A-allele in CYP3A5
• A missing CAT copy in the NR1l3haplotype
• A TCG copy in the ABCB1 haplotype

Carriers vs. non-carriers (n=95)

• Median PFS 13.1 vs. 7.5 months (p=0.001)
• Median OS 19.9 vs. 12.3 months (p=0.009)

Pharmacokinetic but not pharmacodynamic polymorphism are independent predictive factors for PFS in sunitinib treatment mRCC patients.

Polymorphisms in genes encoding for metabolizing enzymes, efflux transporters and drug targets are associate with sunitinib related toxicities.

Genetic polymorphisms in VEGF-A and NOS3 independently predict sever hypertension in sunitinib treated patients.

Clinical Applications of Genomic Classification of Renal Cell Carcinoma:  Selection of Front-line Therapy

Brian I. Rini, MD

Clinical application:

• DNA:  VHL gene status, PBRM1 mutations, SNPs in relation to outcome and toxicity w/ VEGF-targeted therapy
• RNA:  gene expression associated with recurrence after nephrectomy for localized RCC.
  • In initial stages of prognostic and predictive discovery.  Clinical relevance and predictive potential need further investigation.

Response and VHL status:  there is VHL inactivation in the vast majority of clear cell RCC, perhaps not as useful as a discrimination tool for considering therapy. 

PBRM1:  40% clear cell have the mutation—this is a recent discovery and the clinical relevance is to be determined. 

In pazopanib trials IL-8 gene stands out as a potential marker.  SNPs IL8, FGFR2, VEGFR3, VEGFA, and NR1l2 were associated with overall survival in pazopanib-treated RCC patients.

Pooled data is needed to advance our understanding (this effort is underway)

Our understanding of genetic mutations continues to evolve. 

Role of Surgery in Treatment Naïve Metastatic RCC (mRCC)

Cytoreductive Nephrectomy is Best Initial Treatment, Gerald Mickisch, MD

Several trials were reviewed.  The CARMENA trial was a phase III study in which 576 patients with CC mRCC are to be randomized to nephrectomy + sunitinib or sunitinib alone.   The primary endpoint is overall survival.  EORTC-GU study SURTIME looks at TKI before or after nephrectomy.  Anticipate enrolling 440 patients.  OS is the primary endpoint.  So far few patients are enrolled in either trial. 

Surgical therapy in RCC:  either curative, for non-metastatic RCC or as part of the overall treatment plan for those with metastasis at the time of diagnosis.  In non-metastatic disease surgery is the most effective treatment.  Radical surgery does not protect one from metastasis.  Surgical intervention in metastatic RCC improves PFS and OS but is not curative.  It does prolong the lifespan and palliate symptoms. 

Risks of targeted agents in the presurgical setting:  tumor progression on medication—may lead to more complex surgery or overall deterioration of the patient’s condition.  Rapid tumor shrinkage may lead to extensive fibrosis in the retroperitoneum.  Possible increased risk of bleeding/thrombocytopenia.  Wound healing may also be impaired.    

Argument for nephrectomy:  treatment or prevention of tumor related complications, removal of potential source of metastasis, spontaneous regression of mets, reduction of tumor burden/efficacy of systemic therapy, quality of life, improvement in OS,

At this time tumor/nephrectomy followed by systemic therapy is the standard of care for CC mRCC and good PS.  Final message:  Initial cytoreductive nephrectomy is here to stay.

Systemic Therapy is the Best Initial Treatment

Eric Jonasch, MD

The current standard of care for those with mRCC is cytoreductive nephrectomy.  Despite this standard most patients still die of their disease.  So the question posed is why do we have this standard and is it applicable given the recent advances in the treatment of mRCC? 

Nephrectomy followed by immunotherapy improves OS in SELECT patients.  Systemic therapy prior to nephrectomy can be viewed as a litmus test.  If no response to therapy then nephrectomy would not be offered.  Research has demonstrated the benefit of targeted agents exists without a nephrectomy so patients would not lose the benefit of therapy.  We can potentially shrink the primary tumor with current agents—newer agents potentially better.   Dr. Jonasch argues that presurgical therapy is the best overall choice in 2011 in the context of a robust research environment.

Dr. Jonasch provided a review of some of the research—nephrectomy followed by interferon alpha improved survival but the benefit decreased for patients in poor risk groups.  In a study that included 50 patients with mRCC who had resectable primary tumors, patients received bevacizumab for 8 weeks or bevacizumab and erlotinib for 8 weeks.  If they had responsive or stable disease or progressive disease with good PS then surgery was done (new treatment was offered for progressing disease, same treatment continued if stable or responsive disease.  In cases of progressive disease and decline in performance status, patients were offered new treatment or best supportive care.  6 patients did not receive nephrectomy due to progressive disease/worsening performance status.  It is unlikely the patients in this group would have benefitted from upfront nephrectomy.

Other agents, including sunitinib, sorafenib and temsirolimus have shown benefit without cytoreductive nephrectomy.  Primary tumor shrinkage is also noted with these agents.  Newer agents under investigation (axitinib, tivozanib) will likely be even better, but the necessary research needs to be carried out so the agents most likely to downstage tumors can be used. 

Presurgical therapy is relatively safe—effects on wound healing (delay) are associated with bevacizumab and sunitinib.  No significant toxicity has been seen with sorafenib.  There are important trials in development:

EORTC:  458 patients will be randomized to immediate surgery followed with sunitnib therapy (4 weeks on/2 off) or sunitinib, then surgery followed by another course of sunitinib.  Enrollment will occur over 36 months.  The final analysis will be performed after observation of 380 progressions or deaths with a minimum 1/5 year follow up for all patients.

In conclusion, nephrectomy followed by immunotherapy improves overall survival in select patients, but nephrectomy benefits only select patients—therefore systemic therapy could serve as a litmus test.  The benefit of targeted agents exists without nephrectomy, and the primary tumor can be reduced with targeted agents.  In good risk patients with large or unresectable tumor pretreatment may enable patients to be considered resectable or decrease surgical morbidity.  For poor risk patients, pretreatment is a litmus test to see if status improves, then additional options can be considered.

Conclusion

Dr. Christopher Wood, moderator of session

2 sentinel questions for integration of surgery and systemic therapy in mRCC:

• Is there still a role for nephrectomy in the setting of targeted therapy?
• If there is a role for nephrectomy, what is the best timing?

In expanded access trial of mRCC patients with or without prior nephrectomy:  patients with prior nephrectomy had better progression free survival (12 months vs. 6.5 mos) and improved overall survival (19 months vs. 11.1 mos.).

Upfront cytoreductive nephrectomy in properly selected patients remains standard of care.  Presurgical therapy may allow for better patient selection for surgery (initial investigations suggest it is safe).

Management of Side Effects in Patients with Advanced RCC

Nursing Issues in Toxicity Management

Laura Wood, RN, MSN, OCN

Nursing management of patients with mRCC include potential drug interactions, contrast-induced CKD and nutritional support.  Patient education includes potential drug interactions.  These include cytochrome p450, p-glycoprotein (PGP) and UDP glucuronosyltransferase (UGT).  There are inducers, inhibitors and substrates. 

Resources for researching potential drug interactions were reviewed and include Lexicomp, Up to Date, Drugs.com, and others.  Medication diaries are available from some sites for patients to use to list medications and note side effects. 

Expression of membrane targets on nephrons were reviewed, as were stages of chronic kidney disease (CKD).  Assessment of CKD includes serum creatinine.  It should be noted, this is slow to rise following renal injury.  Estimated GFR is the most accurate assessment:  it is recommended by the National Kidney Foundation to screen for and to stage CKD.

Among the many priorities for patient management is the preservation of renal function.  Hypertension contributes to the progression of CKD and end-stage renal disease (ESRD).  The National Kidney Foundation recommends maintaining BP <130/80.  This requires the management of hypertension that is preexisting and/or treatment induced.  Also recommended is dietary sodium restriction to <2 grams per day.  Education surrounding self care is very important.

Nephrogenic systemic fibrosis is a rare disorder that primarily affects the skin causing hardened skin, flexion contractures and limited range of motion.  This condition should be kept in mind for patients who are undergoing serial imaging.  In 2006 the FDA advised the use of gadolinium contrast agents only in cases where diagnostic information is essential and not available with non-contrast enhanced MRI. 

Contrast-induced nephropathy:  serum creatinine begins to rise within 1^st 24 hours, peaks at 3-7 days.  It returns to baseline within 1-2 weeks.  Patients at risk include those with preexisting renal insufficiency, dehydration, hypertension, diabetes mellitus with renal insufficiency, concurrent use of nephrotoxic drugs, age >70, cardiovascular disease and large contrast volumes. 

The Cleveland Clinic Foundation recommends the following renal prophylaxis:  patients with eGFR <45 with risk factors for CKD:  maximize oral fluids (64 oz daily), 1 liter NS IV over 1 hour pre-CT (unless heart problems) and low osmolar non-ionic contrast agent.

• Additionally, N-acetylcyteine may be given twice daily the day before and day of procedure.  Metformin (Glucophage) is held the day of and 48 hours after imaging. 

GI toxicity occurs with therapy and can compound renal dysfunction.  It includes diarrhea, nausea/vomiting, mucositis, taste changes and anorexia.  Management strategies include dietary intervention—encourage use of supplements such as Ensure, Benecal, etc.  Loperamide (Imodium) is used for management of diarrhea.  If ineffective other agents such as diphenoxylate and atropine (Lomotil) or tincture of opium may be used.  Probiotics, pancreatic enzyme therapy may help.  Electrolyte support may be needed, also oral repletion with pedialyte.

Cardiotoxicity of Treatment of Metastatic RCC

Dr. Jean-Bernard Durand

Cardiovascular disease is the number 2 killer in cancer survivors.  There are many definitions of cancer survivor—for a cardiologist the definition of survivor beings at the time of diagnosis. 

There have been 14 FDA approved targeted therapies.  TKI’s have been used for <10 years.  In more than 90 TKI studies registered with FDA in cancer clinical trials, >50% have pathways that are shared in cardiac signaling.  Dr. Durand reviewed the classification of heart failure, noting the elevation of risk for those treated with cardiotoxic therapy and management guidelines.  The definition of hypertension varies.  JNC 7 BP Classification was reviewed.  Cardiovascular mortality risk DOUBLES with each 20/10 mmHg increase in BP.  The impact of high normal BP (130/80-90):  increased incidence of cardiac event or disease. 

Rotational forces that take place in the cardiac cycle were reviewed.  In cardiac imaging, strain or speckle tracking precedes decrease in ejection fraction and may be a useful biomarker. 

Drug induced cardiotoxicity of target cancer therapies for RCC were reviewed.  Sorafenib, sunitinib, and bevacizumab action occurs on PDGF.  Hypertension and CHF occur in a significant percentage of patients.  Sunitinib’s target is VEGF and PDGF with 50% of patients developing hypertension and 3-21% CHF.  Bevacizumab target is also on VEGF and PDGF with hypertension 34% and CHF 2-14%.  Pazopanib has similar rate of hypertension at 47%.  Hypertension appears to respond to ACE Inhibitors or beta blockers regardless of type of targeted agent. 

A study by Rini and colleagues was discussed—Hypertension is a Biomarker of Efficacy in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib.  A higher number of patients achieved an objective response, with better PFS and OS if they had SBP>140 mmHg.  Similar findings were noted for maximum Diastolic BP >90.

In a meta-analysis of phase II and III trials of sunitinib nearly 7000 patients evaluated had grade 3 cardiotoxicity.  The overall incidence of high grade CHF in sunitinib treated patients was 4.1% with relative risk 3.30 vs 1.81 in patients treated with sunitinib vs. placebo.

VEGF hypertension management key points:  small reductions in BP may result in large risk reductions for cardiovascular events.  This means decreased incidence of stroke, myocardial infarction and heart failure.  It is recommended patients at risk for heart failure are treated aggressively prior to starting TKI therapy.  Treating hypertension doesn’t appear to reduce efficacy of cancer therapy.

Dermatologic Adverse Events

Mario E. Lacouture

Globally there are 209,000 RCC cases.  Prior to therapy 45 % have skin findings—range includes tinea pedis/onychomycosis, xerosis, pruritus, and pyoderma.  Some therapies are also associated with muscositis, erythema, impaired wound healing and alopecia.  Patients experience not only psychosocial impact, but financial burden and may need dose reduction for symptom management.

Side effects related to TKI therapy:

Hand-foot skin reaction—acutely occurs within 45 days in >90% of patients.  Involves painful, hemorrhagic bulla and tends to be localized to areas of friction / pressure.  Late presentation is defined as occurring after 45 days.  Involves hyperkeratosis, tender lesions that follow blisters.  Also occurs in areas of friction or pressure.

Management of skin toxicity (hand/foot skin reaction) includes:

• Topical:  urea 40%, salicylic acid 6%.  These are keratolytic, softens hyperkeratosis resulting in decreased epidermal thickness and proliferation.
• Corticosteroids (high potency):  inhibits inflammation, decreases keratinocyte proliferation.

Treatment depends on grade of toxicity:

• Grade 1 (minimal skin changes, no pain): use topical urea 40$ OR salicylic acid 6% twice daily.
• Grade 2 (changes including peeling, blisters, edema or hyperkeratosis with pain, limiting some adl):  topical steroid and oral analgesic.
• Grade 3 (ulcerations, or skin changes with pain interfering with function.  May include severe skin changes—peeling, blisters, bleeding):  topical steroid, oral analgesia. 

There is some evidence that changes in skin microvascular density associated with hypertension may predict clinical outcome.

Skin toxicity also occurs with mTOR inhibitors:  as much as 27 % of patients, 1% grade 3 for everolimus.  For temsirolimus rash occurs 45.8%, 3.3% grade 3.  Onset is usually within 4 weeks for 85% of patients.  Includes itching, erythematous maculopapules. It is grade 1 or 2 in 85%.  Histology shows nonspecific inflammation.  Treatment consists of oral and topical steroids.  mTOR inhibitors also cause oral stomatitis/mucositis in up to 55% of patients.

Some signs and symptoms of a severe reaction include type 1 reaction (hypersensitivity) in which multi-organ systems are involved, possibly anaphylaxis.  Also seen:  Stevens Johnson Syndrome, TENS, DRESS (drug rash with eosinophilia and systemic symptoms).  It was cautioned that these are patients that should not be re-challenged.

The conclusions:  there is room for further study of dermatologic care in relation to RCC therapy.  Early/proactive approaches are advised, and it will be important to characterize derm conditions particularly for adjuvant setting, dose escalation/combination studies and with longer survival, emphasis on quality of life.

Side Effects as Biomarkers of Response

Ulka Vaishampayan, MD

MSKCC prognostic factors / survival were reviewed.  Patients with 0-2 risk factors fared better than those with 3, 4 or 5.  Heng prognostic criteria also reviewed.  Again, those in the favorable category had longer overall survival compared with those in intermediate or poor risk groups.  However, none of the pathologic biomarkers are validated for use in clinical practice:  histopathology, CA IX, PTEN, VEGF, EMT, SNPs associated with VEGF inhibitors, HIF-1.

Common side effects of VEGF inhibitors include hypertension, GI, Thyroid dysfunction and skin toxicity.  Side effects of mTOR inhibitors include hyperglycemia, mucositis, increased lipid profile and pneumonitis.

Axitinib used for patients with different solid tumors including RCC had a higher likelihood of response and longer PFS with diastolic BP >90 (Rini 2008).  Patients with thyroid function abnormalities also had a higher chance of benefit with axitinib (also seen with sunitinib).  Every 10 mm increase in DBP increased the chance of response.  Pharmacokinetic studies indicate this response is independent of drug levels achieved.  This requires validation in larger trials.  One of the questions is should we escalate doses to achieve increase in DBP and will that change response?  Randomized trials would be required.  There is an ongoing axitinib trial looking at this question.

Other research of possible biomarkers was reviewed.  This included neutropenia and thrombocytopenia during treatment as a biomarker of sunitinib efficacy in mRCC patients.  OS survival was improved with grade 2 or higher neutropenia.  This, along with thrombocytopenia could be considered biomarkers predictive of sunitinib efficacy in patients with mRCC, but requires additional investigation.  The results do provide further validation for the use of baseline levels of neutrophils, platelets and hemoglobin as prognostic factors and the change as predictive markers for survival in patients with mRCC treated with sunitinib.

Conclusions:

Side effects as biomarkers would be a good way to optimize targeted therapy due to ease of use, clinical methods of assessment.  Would also help define refractory population early to consider other therapies.  Side effect assessment is generally noninvasive and low cost.  Warrants future investigation in large randomized trials such as those ongoing:  AXIS and COMPARZ.

Summary Discussion

Janice P Dutcher, MD

Management of side effects in RCC treatment.

Chronic renal insufficiency is likely an underappreciated complication of RCC and should be anticipated.  This includes a proactive approach with consideration given to multiple comorbidties.  EGFR should be monitored, hypertension controlled.  Care must be taken with imaging contrast.

For dermatologic side effects proactive management may help extend anti-tumor therapy.  Understanding the mechanism may aid in management.

Cardiac toxicities include hypertension, decreased ejection fraction, compounded in those with pre-existing cardiac disease.  Questions include reversibility when therapy is discontinued and can proactive management extend anti-tumor therapy.

Outcome:  there are models for clinical predictors of survival—MSKCC, CCF, Heng, KCA Consortium.  Moving forward it will be important to further define molecular pathways for clear cell and non clear cell histology.  Could impact treatment decisions.