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Summaries: International Kidney Cancer Symposium
Progressive Disease After Front-Line VEGF Therapy
(Dr. Samad Sadeghi, Dr. Martin Gore, Dr. Jorge Garcia, Dr. Robert Figlin)
- Dr. Sadeghi presented a case describing a patient who had achieved a partial response after 10 cycles of Sunitinib but developed progressive metastatic disease a few years later. This set the stage for a discussion about current therapies; mTOR inhibitors and VEGF inhibitors.
Dr. Gore presented information about mTOR inhibitors.
- Sequencing – VEGF targeted drug followed by an mTOR inhibitor then VEGF targeted drug
- There are data that show activity with VEGF targeted therapy followed by mTOR inhibition
- Second line VEGF versus mTOR showed no significant differences
- There are multiple on-going studies comparing VEGF/mTOR sequencing
- There are currently no randomized clinical trials comparing VEGF inhibition to mTOR inhibition
- Dr. Gore recommends alternating therapies before disease progression
Dr. Garcia presented information about VEGF targeted therapy
- There are no durable and/or complete responses with VEGF inhibitors
- There is no single pathway for disease growth and resistance
- Existing data suggest that both mTOR and VEGF inhibitors are active agents after initial VEGF failure; failure of prior agent does not mean that you cannot be rechallenged with the same agent again
- Axitinib showed better response rates compared to Sorafenib
- Defining resistance disease is challenging but work is in progress; need to define the biology of resistance and how patients fail primary therapy
- Intolerance does not mean resistant disease
- Most patients will see all active/available agents during the course of their disease
Molecular Biology and Pathology
(Dr. Miguel Rivera)
- Wilms Tumors are the most common among children. Of all pediatric renal tumors, 85% are Wilms.
- Males and females are affected at the same rate
Surgery for Pediatric Renal Tumors
(Dr. Peter Ehrlich)
- Wilms tumors are the most common among children
Spread of Wilms tumors
- Lung (80%), Liver (15%), Other (5%)
- Renal Vein, Inferior Vena Cava, Atrium (10%)
- Tumors in both kidneys occurs in 10% of patients
- Metastatic sites
Imaging to determine extent of disease
- Chest CT will pick up 25% more lesions than conventional chest X-ray
- MRI may also be beneficial
- Doppler ultrasound is useful in assessing tumor thrombus in the blood vessels
- Stage 1: Tumor is limited to the kidney and is completely resected
- Stage 2: Tumor extends beyond the kidney and is completely resected
- Stage 3: There is residual tumor following surgery that is confined to the abdomen
- Stage 4: Disease has spread to other areas of the body (lung, liver, bones, etc.)
- Stage 5: There is tumor present in both kidneys at the time of diagnosis
- Vascular extension: Using chemotherapy before surgery my help by decreasing tumor size but frequency of complications is similar to patients who did not receive pre-operative chemo
- Surgery alone may be adequate treatment for very low risk infants; children younger than 24 months with small (< 550 g) Wilms tumors with favorable histology
- Failure to biopsy lymph nodes may lead to increase in disease recurrence
- Tumor spill at the time of surgery significantly increases the risk of local relapse
- Biopsy of the tumor is only warranted when the tumor is deemed non-resectable
- Too big (but how big is too big)
- Extension of tumor thrombus above the level of the hepatic veins
- If removing the tumor requires removal of other organs (spleen, pancreas, colon)
- Pulmonary compromise due to wide-spread lung metastasis
- Partial nephrectomy can be considered for patients with bilateral Wilms tumors or unilateral patients with high risk
- Procedure must be done correctly
- The kidney cannot be minced and brought out in a bag
- Consider chemotherapy before surgery for large tumors
Current Systemic Therapy for Pediatric Kidney Tumors
(Dr. Jeffrey Dome)
Disease control vs. toxicity
- Cardiotoxicity – Increased risk of congestive heart failure at 20 years
- Possibility of a second malignancy increases at 15 years after Wilms diagnosis
- Hepatotoxicity – Veno-Occlusive Disease is seen, currently, in about 3% of patients with current treatments
- Pregnancy/Fertility – Risk of infertility with whole abdomen radiation and risk of congenital abnormalities with flank radiation
- Toxicities include:
Small Stage I Wilms Tumor
- From 1995-2002, the National Wilms Tumor Study Group (now part of the Children’s Oncology Group) Trial looked at surgery-only in patients who were less than 24 months old with Stage 1, favorable histology Wilms tumor where the tumor weighed less than 1.2 pounds. The study was closed and patients were treated with Vincristine and Actinomycin D. Long term follow up revealed a five-year Event Free Survival/Overall Survival of 84%/98% for the patients who were treated with surgery alone. For the patients who had chemotherapy, the Event Free Survival/Overall Survival rates were 97%/99%. Gene mutation significantly affects relapse rate.
Favorable Histology Wilms Tumor with LOH (Loss of Heterozygosity)
- Loss of heterozygosity is a genetic mutation that may delete or change tumor suppressor genes. Genetic testing has allowed treatments to be tailored to the specific situation of the patient potentially affecting survival. However, loss of heterozygosity is associated with worse outcomes.
Stage IV Wilms Tumor
Patients in this group who had a complete response to therapy within 70 days had better 5-year Event Free Survival and Overall Survival compared to the group that didn’t have a complete response in the first 70 days. The National Wilms Tumor Study Group (NWTSG) now recommends the following for Stage 4 patients with disease spread to the lungs:
- Treatment with Actinomycin D, Vincristine, and Doxorubicin
- Radiation treatment to the lung(s)
The European group recommends the following for these patients:
- Treatment with Actinomycin D, Vincristine, and Doxorubicin
- Radiation treatment to the lung(s) only if chemotherapy did not produce a complete response
- 5-year recurrence free survival is improved with both the 3-drug chemotherapy treatment and lung radiation and the 3-drug regimen showed better response than the 2-drug treatment of Actinomycin D + Vincristine.
- Patients in this group who had a complete response to therapy within 70 days had better 5-year Event Free Survival and Overall Survival compared to the group that didn’t have a complete response in the first 70 days. The National Wilms Tumor Study Group (NWTSG) now recommends the following for Stage 4 patients with disease spread to the lungs:
Anaplastic Wilms Tumor
- 4-year Recurrence Free Survival goes down as Stage increases
- Survival is also affected by chemotherapy regimen
RCC in pediatrics
- 6% of tumors in children and adolescents, clear cell uncommon, translocation 50%
Better survival with lymph node involvement
- 72% RCC with lymph node involvement had a durable survival
- 14/15 with translocation RCC and lymph node involvement had a durable survival
- There is an ongoing study for pediatric RCC
(Dr. John Kalapurakal)
Guiding Principles of Cancer Therapy
- Good quality survival
Risk-based treatment approach
- Minimize therapy, maintain high cure rates, minimize toxicity
- Intensify therapy, increase cure rates, balance with “acceptable” toxicity
- Low-risk tumors
- Limit radiation doses to critical structures
- Radiation Therapy doses are based on patient age
From the National Wilms Tumor Study-1 (NWTS-1)
- Post-operative radiation therapy not necessary for children under 2 years old however, abdominal recurrence rates were higher with radiation therapy in older children
- Recurrence free survival was better with radiation and chemotherapy together than for either alone
From the NWTS-2
- Age did not influence outcome as was seen in the previous study
- Duration of chemotherapy (6 vs. 15 months) did not influence survival
- Children with stage 2 Favorable Histology tumors do not need radiation or Adriamycin in addition to Vincristine + Actinomycin D.
- Children with stage 3 Favorable Histology tumors 10 Gy of radiation + Adriamycin, Vincristine, and Actinomycin D had similar survival to those who had 20 Gy of radiation
- Radiation and Adriamycin were eliminated in 60% of children
- Flank radiation doses were decreased from 40 Gy to 10 Gy
- Newer radiation therapy techniques, such as Intensity Modulated Radiation Therapy (IMRT) have decreased the risk of stray radiation to adjacent organs
Timing of radiation therapy
- Favorable Histology cases should start radiation, preferably, by day 9 but not later than day 14
- Unfavorable Histology cases should start radiation no later than day 9
- In patients who had tumor spillage at the time of surgery, recurrence is more commonly seen in the flank area
Whole Lung Irradiation (WLI)
- Event-free and overall survival is better in patients with WLI compared to no WLI
Late toxicities from radiation therapy
- Abdominal organs and vasculature
- Pelvic organs (ovaries, uterus)
- Second malignancies
Long Term Follow-up and Outcome
(Dr. Daniel Green)
Causes of mortality of Wilms tumor survivors
The National Wilms Tumor Study Group has compiled data from all five of the studies done for Wilms Tumor patients from 1969-2002 (9240 patients) and has investigated outcomes.
- 782 patients died before 5 years from diagnosis related to either the original cancer or another cancer that arose. 91 patients died after 5 years from diagnosis related to the original cancer or another cancer that arose.
- 11 patients died before 5 years from diagnosis related to heart or lung problems or kidney failure. 30 patients died after 5 years from diagnosis related to heart or lung problems or kidney failure.
- 7 patients died before 5 years from diagnosis related to external causes. 16 patients died after 5 years from diagnosis related to external causes.
- Five-year survivors of Wilms tumor are 4.9 times more likely to die and 4.7 times more likely to have grades 3 or 4 chronic health condition than their same sex siblings.
- Survivors of Wilms tumor have increased risks for hypertension and congestive heart failure.
- The risk of end-stage renal disease is increased in Wilms tumor survivors with specific syndromes and those with bilateral Wilms tumor.
- The National Wilms Tumor Study Group has compiled data from all five of the studies done for Wilms Tumor patients from 1969-2002 (9240 patients) and has investigated outcomes.
Chronic medical conditions related to Wilms tumor treatment
- Subsequent malignant neoplasms
Congestive heart failure
- 4.4% at 25 years
- Females affected more than males
End-stage renal disease
- Chronic dialysis
- Renal transplant
- Hypertension complicating pregnancy and malposition of the fetus were more frequent among irradiated women and was related to radiation dose
- Early threatened labor
- Radiation may affect birth weight
- The offspring of irradiated female survivors of Wilms tumor have an increased risk of premature birth
Health status and health care practices of survivors of Wilms tumor
- Wilms Tumor survivors were more likely to have a general medical exam within the last two years and were more likely to have ever had a mammogram than their siblings.
- Other health practices, such as a clinical breast exam or PAP smear were not statistically significantly different from their siblings. Female survivors at increased risk for breast cancer do not undergo mammography more frequently than female siblings.
(Dr. Andrew Wagner)
- The diagnosis of renal cell cancer is usually made as an incidental finding when patients are having a scan or x-ray done for some other condition. However, some patients do present with symptoms that may include blood in the urine, pain, or a palpable mass; there may be other noticeable effects on the body as a result of the cancer spreading to other areas. After a diagnosis of kidney cancer is made, a staging evaluation is mandatory to see the extent of the cancer. This will usually include a battery of lab tests along with x-rays, CT scans and/or MRI’s. In very specific cases, a biopsy may be done of the kidney or a metastatic site. Once staging is complete, a thorough discussion should take place with your doctor regarding the plans for surgery and possibly other treatments.
The purpose of the initial evaluation is:
Evaluate patient for signs and symptoms of Renal Cell Carcinoma (RCC)
- > 50% are an incidental finding and most of these are low stage
- <50% present with signs & symptoms of RCC and most of these are at an advanced stage
The patient history is looking for:
- Blood in the urine
- Abdominal or flank pain
- Scrotal swelling
- Weight loss
- Night sweats, fever, or malaise
- New back or bone pain
- Mental status changes
- Persistent cough
Social risk factors include:
- History of smoking (increases risk and accounts for 10-30% of RCC)
- Obesity (increases risk and accounts for 30-40% of RCC)
- High blood pressure
- Long term dialysis
Suspected risk factors include:
- Low physical activity
- Alcohol consumption (however, there is a 28% reduction with one drink per day)
- Occupational exposures such as Trichloroethylene
- Pregnancy – there is a 40-90% increase in women who have had children compared the those who have never been pregnant
- Most cases of RCC are sporadic (97%)
- Familial causes: Von Hippel-Lindau, Hereditary Papillary RCC, Birt-Hogg-Dube syndrome
- There is a 2X higher risk if there is a first degree relative
- If the physical exam reveals an abdominal mass, varicocele, lower extremity edema, or enlarged lymph nodes, this is usually an indicator of advanced disease
Stage primary tumor
- Stage 1 = tumor less than or equal to 7 centimeters
- Stage 2 = tumor greater than 7 centimeters and contained in the kidney
- Stage 3 = tumor spread into Gerota’s fascia or tumor thrombus into the inferior vena cava
- Stage 4 = tumor spread to lymph nodes or other organs
- Abdominal CT or MRI is used to evaluate tumor location and spread, if any
- Chest X-Ray is usually sufficient (Chest CT if advanced disease or abnormal X-Ray)
- Other studies are ordered as deemed appropriate
Evaluate for metastasis
Kidney metastatic sites:
- Lung (69%)
- Liver (34%)
- Bone (43%)
- Lymph nodes (22%)
- Adrenal (19%)
- Brain (7%)
- Other (<1%)
- Kidney metastatic sites:
Surgical planning to evaluate the feasibility of:
- Cytoreductive surgery
- Nephron-sparing surgery
Role of biopsy
- Consider when it may impact disease management
- Evaluate patient for signs and symptoms of Renal Cell Carcinoma (RCC)
(Dr. Ivan Pedrosa)
New Imaging Strategies
There are multiple new imaging techniques including ultrasound, CT, PET, and MRI scans that are providing better images allowing for differentiation of tumor types.
- Contrast enhanced Ultrasound helps with tumor type differentiation
- CT Dual energy source used to create a virtual non-contrast view
- Dynamic Contrast Enhanced Imaging (CT or MRI)
- Arterial spin labeling MRI (done without contrast)
- Diffusion Weighted MRI
- There are multiple new imaging techniques including ultrasound, CT, PET, and MRI scans that are providing better images allowing for differentiation of tumor types.
- Correlation Between Imaging and Pathology
- Correlation with Clinical Outcomes
Neoadjuvant (pre-surgical) Therapy
(Dr. Cristina Suarez Rodriguez, Dr. Christopher Wood, Dr. Arie Belldegrun)
Dr. Rodriguez presented a case for discussion of whether or not pre-surgical chemotherapy was appropriate
- May be appropriate in select patients to down-stage tumor.
- (How do you decide which patients are appropriate or good candidates for neoadjuvant treatment?)
- Dr. Christopher Wood presented a PRO stance on the use of neoadjuvant treatment for locally advanced RCC. Even though neoadjuvant treatment has been used successfully in other cancers, there is no data at this time that proves that it is useful in down-staging tumors or in preventing disease recurrence in the future. There are data to suggest that it is safe to use from a surgical standpoint. Currently there are several ongoing or recently completed clinical trials looking into the effectiveness of targeted therapies in the adjuvant setting but the results of these studies is still years away. New treatments on the horizon may hold more promise. The concept of neoadjuvant therapy is one that deserves further investigation in the form of well-designed clinical trials. There is some evidence that points to the use of neoadjuvant treatment as a prognostic indicator. Patients who progress while on targeted therapy will probably not do well regardless of surgery. However, patients who have a significant response (>10%) in their primary tumor are more likely to have an improved outcome. Bottom line: neoadjuvant therapy has been proven to be safe but it has not been very successful at shrinking tumors before surgery…this is not the standard of care.
- Dr. Ari Belldegrun presented the CON stance on the use of neoadjuvant treatment for locally advanced RCC. There may be a small group of patients that would be appropriate candidates for neoadjuvant treatment; high risk patients with localized disease or unresectable patients that may become resectable after neoadjuvant therapy. Depending on treatment regimen, toxicities may be significant. Tumor reduction is not clinically significant. Response to treatment did not alter the surgical approach. There is no appreciable pathological difference between patients treated with neoadjuvant therapy versus those who were not treated. There is no evidence of improved survival at this time with neoadjuvant treatment. Neoadjuvant treatment should only be done in the context of a clinical trial.
- Dr. Steven Campbell summarized the PRO/CON discussion of neoadjuvant therapy. He indicated that 40-70% of patients will have a 10-20% response with neoadjuvant treatment. Ongoing clinical trials are looking into neoadjuvant treatment to determine the utility, or lack thereof, of this treatment option.
Lymph Node Dissection
(Dr Simon Kim, Dr. Michael Blute, Dr. Scott Eggener, Dr. Swanson)
- Dr. Kim presented two cases to stimulate the discussion of whether or not removing lymph nodes during nephrectomy was appropriate.
Role of Lymph Node Dissection in RCC
- There are data supporting that the removal of lymph nodes may improve survival in patients with RCC with metastatic disease in the lymph nodes.
A review of over 1600 cases of radical nephrectomy for non-metastatic RCC revealed certain features that were predictive of lymph node involvement:
- Nuclear Grade 3 or 4
- Sarcomatoid component
- Tumor > 10 cm
- Stage pT3 or pT4
- If 0-1 features are present, 0.6% node positive
- If ≥ 2 features are present, 10% node positive
- If all 5 features are present, 53% node positive
Recommendations for Lymph Node Dissection
- If there is a low risk primary tumor, there is no benefit
- High risk primary tumor with enlarged lymph nodes, retroperitoneal lymph node dissection should be done
- High risk primary tumor, retroperitoneal lymph node dissection should be done
- Nephrectomy to reduce tumor burden, retroperitoneal lymph node dissection should be done
- Isolated retroperitoneal recurrence or development of a new tumor, retroperitoneal lymph node dissection should be done
- Conclusion: there is no increased risk of doing the lymph node dissection early on.
- Lymph node dissections rarely done, even for large tumors, because there is no proven therapeutic or staging benefit for low risk patients. A Mayo study revealed no data showing therapeutic benefit in high risk patients. For clinically node negative high risk patients, there is staging value but no proven therapeutic benefit.
- Rate of positive nodes is associated with stage and grade; the higher the stage and grade, the more likely there will be positive nodes. A tumor > 10 cm with sarcomatoid features and tumor necrosis is also associated with positive nodes.
- Looking at several studies, the percentage of patients that were found to have positive nodes at the time of surgery was relatively small in all but one study. The 5-year cancer specific survival for these patients was very consistent at 35-39%.
- According to the National Comprehensive Cancer Network guidelines for kidney cancer, “Regional lymph node dissection is optional but is recommended for patients with adenopathy on preoperative imaging or palpable/visible adenopathy at time of surgery.”
- Lymph node dissection for patients with clinical node negative T1-T2 disease is proven not to be necessary
- Lymph node dissection for patients with clinical node negative T3-T4 disease is reasonable but of unproven therapeutic benefit
- Lymph node dissection for patients with clinical node positive non-metastatic disease is reasonable but of unproven therapeutic benefit
- Metastatic disease in the lymph nodes without metastatic disease elsewhere is rare.
- If doing a lymph node dissection, taking more nodes increases the rate of finding at least one node positive
- For clinically positive nodes, an extended lymph node dissection may improve benefit
Prognosis, Risk Stratification, and Surveillance
(Dr. Vincenzo Ficarra)
Prognostic factors in localized RCC
- Performance Status: worse performance status correlates to poorer survival
- Symptoms present at diagnosis: patients with local and/or systemic symptoms at presentation have poorer survival
- Clinical tumor size
- Clinical stage (cTNM)
- Tumor size and extension (TNM)
- Histologic subtype: Papillary and chromophobe subtypes have better survival than clear cell
- Fuhrman grading: as Fuhrman grade increases, survivability decreases (papillary and chromophobe types use a different grading system)
- Necrosis: survival is better with a non-necrotic tumor
- Sarcomatoid features: Sarcomatoid features correlate to poorer survivability
- Microvascular invasion
- The use of prognostic integrated systems based on traditional clinical and /or pathological parameters improve prognostic accuracy and help guide surveillance and/or treatment after nephrectomy
- Currently, there is no general consensus on follow up, however the National Comprehensive Cancer Network has surveillance guidelines
- Clinical (Laboratory)
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