Partial nephrectomy for Wilms tumor: reducing the morbidity of cancer treatment in children

Wilms tumor is a relatively rare form of kidney cancer, but the most common kidney cancer in children, and the fourth most common cancer in children with approximately 500 new cases per year.[1] Historically Wilms tumor carried a poor prognosis, with survival around 30%. Largely due to the efforts of the National Wilms Tumor Study group (NWTS) and the International Society of Pediatric Oncology (SIOP) survival has improved to around 90%. However, treatment often involves radical nephrectomy (surgical removal of an entire kidney) and chemotherapy. Fortunately the improved prognosis of Wilms tumor allows surgeons and oncologists to shift their focus to reducing the morbidity of treatment. Partial nephrectomy (or removing just a tumor and the portion of kidney that surrounds it) has been proposed as a means to reduce the burden of therapy in children with Wilms tumor.

The NWTS group recently released treatment protocol AREN0534, the first official protocol to recommend partial nephrectomy for Wilms tumor. In this protocol, neoadjuvant chemotherapy (chemotherapy given prior to surgery) followed by partial nephrectomy is recommended only for patients in whom preserving renal tissue is essential.  These patients include those with Wilms tumor in both kidneys, a tumor in a solitary kidney, or unilateral disease with predisposing syndromes that increase the risk of recurrence in any remaining kidney.[2]  While partial nephrectomy in lieu of radical nephrectomy is gaining popularity, partial nephrectomy for children with unilateral nonsyndromic Wilms tumor is still considered experimental.

Why partial nephrectomy?

The use of partial nephrectomy in adult patients with renal cell carcinoma has shown improved renal function and comparable oncological outcomes in select patients.[3,4] The benefits of partial nephrectomy (i.e. saving kidney function) in children with Wilms may be of paramount importance given the long expected survival given their young age at diagnosis, possible need for chemotherapy and significant risk of recurrence (2-3%) in the remaining kidney.[5] Surprisingly, the incidence of end-stage renal disease in Wilms tumor patients is low at 0.7%.[6] However, a group in Italy followed a small group of children with Wilms tumor that were treated with a partial nephrectomy and found that at 6 and 12 years of follow-up, patients had better renal function and lower blood pressures than their counterparts that received a radical nephrectomy.[7,8]

Oncologic outcomes

Unfortunately current oncologic data is limited to retrospective studies that are limited by small numbers and selection bias. The largest study examined a European cohort of 807 patients in a protocol that called for neoadjuvant chemotherapy and radical nephrectomy. Fortunately for the purposes of this study, 5% of patients actually received a partial nephrectomy. The relapse rate and relapse-free survival were similar in the partial nephrectomy and radical nephrectomy group, suggesting oncological outcomes were similar in the partial nephrectomy group (figure 1).[9]

Figure 1. Relapse events and Relapse free survival in Wilms tumor patients with 

partial nephrectomy vs radical nephrectomy. Neoadjuvant = Neoadjuvant 

chemotherapy.   Nx = nephrectomy.  Adapted from: Haecker, F., J Urology, 2003.

A group at UTSW (University of Texas Southwestern) reviewed current available literature and identified 82 patients that underwent partial nephrectomy for unilateral Wilms tumor and compared them to 121 of their own patients that underwent radical nephrectomy. They found that recurrence-free survival and overall survival were not significantly different between the partial and radical nephrectomy groups (figure 2). Selection of patients for partial and radical nephrectomy likely played a role in these outcomes (so called selection bias), as the children undergoing partial nephrectomy group had significantly lower stage tumors than patients undergoing radical nephrectomy.[10] Regardless, both studies discussed above suggest that Wilms tumor may be treated with partial nephrectomy without a significant compromise in cancer outcomes.

Cost, N., Pediatric Blood & Cancer, 2012

How many Wilms tumor patients are candidates for partial nephrectomy?

Resectability, or the ability of the tumor to be removed, is subjective and relies on the judgment of surgeons and radiologists. A group at UCONN (University of Connecticut) retrospectively reviewed CT scans and MRIs from Wilms tumor patients that underwent radical nephrectomy. A Cancer Oncology Group (COG) surgeon and radiologist reviewed the image and judged whether partial nephrectomy was feasible. They found that only 8% of patients were amenable to partial nephrectomy.[11] A similar study from UTSW reviewed surgical pathology from children that underwent radical nephrectomy. They determined 24.4% would have been amenable to partial nephrectomy.[12] European studies utilizing neoadjuvant chemotherapy in their protocols demonstrate that tumors can shrink 50 – 60% preoperatively.[13,14] Therefore, it is hypothesized that preoperative chemotherapy could increase the proportion of tumors amenable to partial nephrectomy. Further studies from the new AREN0534 protocol should enhance our grasp of this question.

Location of Wilms tumors in radiographic determination of partial 

nephrectomy feasibility study.  Ferrer, FA., J Urology, 2013

Is Partial Nephrectomy Worth the risk?

Partial nephrectomy does not come without risk. It is technically challenging operation requiring careful dissection and control of the renal vasculature (the kidney gets approximately 25% of the body's blood flow per minute), as well as removal of a tumor with a clean margin, and reconstruction of the kidney – all within a time period that prevents permanent kidney damage. Tumor spillage and positive margins are more common, which result in upstaging of Wilms tumor in these children. Upstaging has implications for prognosis and morbidity. According to COG protocols, positive surgical margins result in radiation and longer chemotherapy, while spillage results in a longer chemotherapy regimen. The risks and benefits must be carefully considered before proceeding with partial nephrectomy which, once again, remains an experimental therapy for unilateral nonsyndromic Wilms tumor.

Summary

Wilms tumor survival has increased significantly allowing urologists to focus on reducing the burden of therapy. The increasing use of partial nephrectomy in adults opened the door for consideration in children. A small portion of Wilms tumor patients are potential candidates for partial nephrectomy. Future data from partial nephrectomy patients in protocol AREN0534 will help us learn about the affect and feasibility of partial nephrectomy for unilateral Wilms tumor. Current data indicate oncologic outcomes appear similar with improved kidney function compared to radical nephrectomy patients.

This blog was written by Kyle Ericson, Medical Student at the University of Chicago.  Kyle recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Partial Nephrectomy for Wilms Tumor" from which this blog is inspired. Kyle is looking forward to a career in urology.


 





References
1.    Grovas A, Fremgen A, Rauck A. The National Cancer Data Base report on patterns of childhood cancers in the United States. Cancer. 1997;80(12):2321 -­‐ 2332. Available at: http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-­‐ 0142(19971215)80:12%3C2321::AID-­‐CNCR14%3E3.0.CO;2-­‐W/full. Accessed August 17, 2014.
2.    Nakamura L, Ritchey M. Current management of wilms' tumor. Curr Urol Rep. 2010;11(1):58-­‐65. doi:10.1007/s11934-­‐009-­‐0082-­‐z.
3.    Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective randomized EORTC intergroup phase 3 study comparing the complications of elective nephron-­‐sparing surgery and radical nephrectomy for low-­‐stage renal cell carcinoma. Eur Urol. 2007;51(6):1606-­‐15. doi:10.1016/j.eururo.2006.11.013.
4.    Scosyrev E, Messing EM, Sylvester R, Campbell S, Van Poppel H. Renal function after nephron-­‐sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904. Eur Urol. 2014;65(2):372-­‐7. doi:10.1016/j.eururo.2013.06.044.
5.    Moorman-­‐Voestermans C. Is Partial Nephrectomy Appropriate Treatment for Unilateral Wilms' Tumor? J Pediatr ….1998;33(2):165-­‐170. Available at: http://www.sciencedirect.com/science/article/pii/S0022346898904250. Accessed August 17, 2014.
6.    Harel M, Makari JH, Ferrer F a. Oncology: the role of partial nephrectomy in Wilms tumor. Curr Urol Rep.
2013;14(4):350-­‐8. doi:10.1007/s11934-­‐013-­‐0330-­‐0.
7.    Cozzi F, Schiavetti A, Morini F, Zani A. Renal function adaptation in children with unilateral renal tumors treated with nephron sparing surgery or nephrectomy. J Urol. 2005;174(December 2003):1404-­‐1408. doi:10.1097/01.ju.0000173132.19010.ff.
8.    Cozzi DA, Ceccanti S, Frediani S, Schiavetti A, Cozzi F. Chronic Kidney Disease in Children With Unilateral Renal Tumor. J Urol. 2012;187(5):1800-­‐1805. doi:10.1016/j.juro.2011.12.109.
9.    Haecker F-­‐M, von Schweinitz D, Harms D, Buerger D, Graf N. Partial nephrectomy for unilateral Wilms tumor: results of study SIOP 93-­‐01/GPOH. J Urol. 2003;170(3):939-­‐42; discussion 943-­‐4. doi:10.1097/01.ju.0000073848.33092.c7.
10.    Cost NG, Lubahn JD, Granberg CF, et al. Oncologic outcomes of partial versus radical nephrectomy for unilateral Wilms tumor. Pediatr Blood Cancer. 2012;58(6):898-­‐904. doi:10.1002/pbc.23240.
11.    Ferrer F a, Rosen N, Herbst K, et al. Image based feasibility of renal sparing surgery for very low risk unilateral Wilms tumors: a report from the Children's Oncology Group. J Urol. 2013;190(5):1846-­‐51. doi:10.1016/j.juro.2013.05.060.
12.    Cost NG, Lubahn JD, Granberg CF, et al. Pathological review of Wilms tumor nephrectomy specimens and potential implications for nephron sparing surgery in Wilms tumor. J Urol. 2012;188(4 Suppl):1506-­‐10. doi:10.1016/j.juro.2012.02.025.
13.    Bogaert GA, Heremans B, Renard M, Bruninx L, De Wever L, Van Poppel H. Does preoperative chemotherapy ease the surgical procedure for Wilms tumor? J Urol. 2009;182(4 Suppl):1869-­‐74. doi:10.1016/j.juro.2009.03.022.
14.    Reinhard H, Semler O, Bürger D, et al. Results of the SIOP 93-­‐01/GPOH trial and study for the treatment of patients with unilateral nonmetastatic Wilms Tumor. Klin Pädiatrie. 216(3):132-­‐40. doi:10.1055/s-­‐2004-­‐822625.

BCG Alternatives for Non-Muscle Invasive Bladder Cancer

Bacillus Calmette-Guerin (BCG) immunotherapy is the standard, most commonly used intravesical treatment for patients with NMIUBC (non-muscle invasive urothelial bladder cancer).  [Please see our prior blog entries on BCG treatment below]  However, upwards of 40% of patients will "fail" intravesical treatment and have a recurrence or progression of their bladder cancer. Due to the aggressive nature of MIUBC (muscle-invasive urothelial bladder cancer), early radical cystectomy is advocated by many urologists who care for patients with progressive disease.  However, radical cystectomy is a morbid and life-changing operation and many patients seek alternative treatments to BCG before submitting to radical surgery.  In addition, some patients cannot tolerate BCG treatment due to side effects.  Finally, in times of shortage (we are currently undergoing a BCG shortage in the US), alternative treatments can be used in lieu of premature radical surgery.

A prior blog entry reviewed Immunotherapy Alternatives to BCG.  Many of these medications are in the experimental phase of investigation and have not been proven to be useful in humans.  In this blog, we review intravesical chemotherapy, device-assisted chemotherapy and thermochemotherapy alternatives to intravesical BCG and the data with each modality.

INTRAVESICAL CHEMOTHERAPY

Mitomycin C (MMC) has long been used for low-grade, non-invasive urothelial cancer of the bladder.  However, MMC has limited efficacy after BCG failure with only 4 of 21 patients responding in a small, Scandinavian study.[1]

Gemcitabine is the standard systemic therapy given to patients with MIUCB.  Two early (Phase I-II) studies demonstrate the potential efficacy of gemcitabine given intravesically.  In one study of 18 patients, 7 demonstrated a complete response (negative biopsy and cytology for cancer) and 4 patients demonstrates a partial response (negative biopsy, positive cytology).[2]  Twenty-two of 39 (56%) patients with intermediate- and high-risk of recurrence after BCG therapy were recurrence free after 6 weeks of treatment.  In addition, none of the non-responders had progression of disease while receiving gemcitabine therapy.[3]

Docetaxel is another systemic chemotherapeutic agent used in advanced cancers. Researchers at Columbia University in New York demonstrated a 59% complete response rate in 32 of 54 patients after 6 weekly cycles (18 patients received maintenance therapy).  This translated into recurrence-free survival rates of 40% and 25% at 1- and 3-years respectively; 25% underwent radical cystectomy; and 5-year cancer-specific survival was 85%.[4]

In preliminary research, the combination of Gemcitabine/Docetaxel demonstrates promising results with lower side effect profiles than other intravesical chemotherapies and with excellent short-term response rates. We are currently using this regimen at Johns Hopkins in patients with BCG failures, refractory disease and in those patients who cannot receive BCG with promising results.

   

DEVICE-ASSISTED CHEMOTHERAPY

Photodynamic therapy (PDT) involves treating the bladder with a photosensitizing medication that selectively binds to tumors and using a strong intravesical light source to destroy tumors.  Five-aminolevulinic acid (5-ALA) was given orally to 24 BCG-failure patients and, after two years, 16 were tumor free.[5]

From Wild P J et al. Mol Cancer Ther 2005;4:516-528

MMC and EMDA (electromotive drug administration) has been demonstrated to enhance the delivery of the medication to the urothelial cells lining the bladder.  Using a pulsed electrode inserted into the bladder via a urinary catheter, 108 BCG-failure patients were randomized to MMC, MMC with EMDA or BCG.  MMC with EMDA demostrated a better response rate (58%) at 6 months than MMC alone (31%), however this was not improved compared to BCG (64%) alone.[6]

THERMOCHEMOTHERAPY

Heating the bladder to 42 degrees Celsius (107 degrees F) while administering MMC has been demonstrated to have some effect in patients with BCG failure.  Using a special microwave and catheter, the recurrence rates have been observed between 14% at 1-year and 24% at 2-years if no prior BCG exposure; and in patients who previously failed BCG treatment, 1- and 2-year recurrence rates were 23% and 41% respectively.[7]  In a study of 15 European centers, the complete response rate was 92% at 1-year but fell precipitously to 50% at 2-years.[8] A recent meta-analysis of 22 studies demostrated a 59% relative reduction in risk of recurrence for all patients with NMIUBC treated with heated MMC compared to MMC alone.[9] 

Thermochemotherapeutic system demonstrated from Lammers etal [9].

SUMMARY

May patients do not continue with intravesical BCG treatments due to "failure" (recurrence or progression of disease), intolerance of the medication or inavailability of the drug.  Reasonable intravesical chemotherapeutic agents include: mitomycin c, gemcitabine, docetaxel and combinations of these medications.  Device-assisted therapeutics and thermochemotherapy remain alternatives.

Availability of BCG alternatives will vary by center and urologist.  Any patient who fails BCG is at high-risk for disease progression and death from urothelial cancer.  A thorough discussion of the alternatives and risk of disease progression should be undertaken prior to embarking on any alternative treatment.

Prior Blog Entries on BCG Therapy:

Success Rates for Intravesical BCG Treatments for Bladder Cancer (2/24/14)
BCG Complications for Bladder Cancer: Who, What, When and How to Treat? (3/12/14)
BCG For Bladder Cancer: Why it Works, How it Works (4/25/14)
BCG Immunotherapy Alternatives (7/16/14)

References

[1] Malmstrom PU, Wijkstrom H, Lundholm C, et al. 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J Urol. 1999;161:1124–7.

[2] Dalbagni G, Russo P, Sheinfeld J, et al. Phase I trial of intravesical gemcitabine in bacillus Calmette-Guerin-refractory transitional-cell carcinoma of the bladder. J Clin Oncol. 2002;20:3193–8.

[3] Gontero P, Casetta G, Maso G, et al. Phase II study to investigate the ablative efficacy of intravesical administration of gemcitabine in intermediate-risk superficial bladder cancer (SBC) Eur Urol. 2004;46:339–43.

[4] Barlow L, McKiernan JM, Benson MC.  Long-term survival outcomes with intravesical docetaxel for recurrent nonmuscle invasive bladder cancer after previous bacillus Calmette-Guérin therapy.  J Urol. 2013 Mar;189(3):834-9. doi: 10.1016/j.juro.2012.10.068. Epub 2012 Oct 30.

[5] Waidelich H, Stepp R, Baumgartner E, et al. Clinical experience with 5-aminolevulinic acid and photodynamic therapy for refractory superficial bladder cancer. J Urol. 2001;165:1904–7.

[6] Di Stasi SM, Giannantoni A, Stephen RL, et al. Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study. J Urol. 2003;170:777–82.

[7] Van Der Heijden AG, Kiemeney LA, Gofrit ON, et al. Preliminary European results of local microwave hyperthermia and chemotherapy treatment in intermediate or high risk superficial transitional cell carcinoma of the bladder. Eur Urol. 2004;46:65–72.

[8] Alfred Witjes J, Hendricksen K, Gofrit O, Risi O, Nativ O.  Intravesical hyperthermia and mitomycin-C for carcinoma in situ of the urinary bladder: experience of the European Synergo working party.World J Urol. 2009 Jun;27(3):319-24. doi: 10.1007/s00345-009-0384-2. Epub 2009 Feb 22.

[9] Lammers RJ, Witjes JA, Inman BA, Leibovitch I, Laufer M, Nativ O, Colombo R. The role of a combined regimen with intravesical chemotherapy and hyperthermia in the management of non-muscle-invasive bladder cancer: a systematic review.  Eur Urol. 2011 Jul;60(1):81-93. doi: 10.1016/j.eururo.2011.04.023. Epub 2011 Apr 20. Review.

Historical Contribution: 1944, Frame & Jewett, 17-Ketosteroids in Prostate Cancer

1944

The excretion of 17-ketosteroids in carcinoma of the prostate E. G. Frame and H. J. Jewett Journal of Urology 1944  52: 330-333.

At the writing of this manuscript, it was known that patients undergoing androgen ablation through bilateral orchiectomy for prostate cancer experienced an oncologic benefit.  As testosterone is secreted by the testes, and then excreted in the urine as 17-ketosteroids, a number of researchers observed that 17-ketosteroid levels fall initially after orchiectomy and then rise within a few months.  This coincides with subjective patients symptoms initially improving and then worsening with time.

Frame and Jewett hypothesized that prostate cancer itself, may impact testosterone/17-ketosteroid levels and sought to determine the influence of prostate cancer on 17-ketosteroid excretion.

Sixteen patients with prostate cancer were compared to 8 patients without the disease.  The data is presented below.  Important observations include:

• 17-ketosteroid excretion decreases with age (levels are lower in men >62 years in this study)
• There is no difference between men: 
• with prostate cancer and controls.
• before and after orchiectomy (all men underwent orchiectomy >10 months prior to analysis).
• A slightly higher Beta-Fraction of 17-ketosteroid in the prostate cancer group is not clinically or statistically significant.

Frame and Jewett allude to the fact that the testis are not the only source of 17-ketosteroid (androgens) and that the adrenal may provide an extragonadal source of androgens in the post-orchiectomy patient.  As they observe that 17-ketosteroids decrease in the aged population, they conclude that either:

1. there is a decreasing contribution of androgen from the testes as men age, OR
2. removal of the testes results in increased adrenal production of androgen (17-ketosteroid).

Click on the link above, visit the Centennial Website or click here to read the original manuscript.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Types of Kidney Stones: Implications for Diagnosis and Treatment

Kidney Stones.

The majority of kidney stones are made of calcium (75%).  However, there are a variety of kidney stones made of calcium and other components that have different etiologies and treatments.  For some stones (i.e. cystine stones), knowing the stone composition provides valuable information to diagnose the cause and initiate treatment of the causative condition.  Since most stones contain calcium, knowing the type of stone and the underlying cause help the practitioner create a rational treatment plan for a given patient.  Read more about the variety of kidney stones in this blog:

Calcium Containing Kidney Stones

As stated above, approximately 75% of kidney stones contain calcium.  The most common calcium containing stones include: calcium oxalate (60%), followed by hydroxyapatite (20%) and the rare, brushite (2%) stones.  The most common metabolic abnormalities associated with calcium-containing kidney stones include:
containing stone is

• hypercalciuria (most common abnormality)
• hypocitraturia
• hyperuricosuria
• hyperoxaluria

In general, these metabolic abnormalities lead to supersaturation of the urine with calcium.  Supersaturation refers to the condition when more solute (i.e. calcium) is in a fluid (i.e. urine) that can be chemically dissolved.  The above conditions either increase the amount of calcium in the urine, alter the pH (acidic content of the urine) or modify the likelihood of stones to form.  

Electron microscopy of calcium
oxalate crystals.

Calcium Oxalate Stones

Both calcium and oxalate are naturally occuring chemicals in the body and the urine.  Therefore, calcium oxalate stones can form with a variety of conditions that lead to increased calcium in the urine (hypercalciuria) and oxalate (naturally found in vegetables, fruits and nuts).  One common factor is that calcium oxalate stones often form when the urine is alkaline (pH>5.5).  

The needle-like crystals of calcium
phosphate in the urine.

Calcium Phosphate Stones

Like calcium oxalate stones, calcium phosphate stones are made of normally occurring components of the urine when the urine pH is alkaline (>7.0).  Calcium phosphate stones are also known as apatite or brushite stones.  Calcium phosphate stones form needle-like crystals in the urine (below).

Non-Calcium Containing Stones

Uric acid crystals.

Uric Acid Stones

Uric Acid (7%) stones form only in acid urine.  People more likely to form uric acid stones have conditions that predispose to acidic urine including: low urine output, a diet high in animal protein (such as red meat), high alcohol intake, and may have obesity, gout or inflammatory bowel disease.

Struvite Stones

The coffin-lid appearance of struvite
stones in the urine.

Struvite (7%) stones are made of ammonium magnesium phosphate.  They have a typical coffin-lid appearance on microscopy. These stones occur in alkaline-urine only, alkaline urine is produced by urease-producing bacteria, therefore these are otherwise known as "infectious stones."  These stones are common in patients with recurring urinary tract infections, especially those with spinal cord injuries and neurogenic bladder, as these patients are predisposed both to UTI and bone metabolism disorders in which calcium is mobilized.

Cystine Stones

Cystine kidney stones.

Cystine (1-3%) stones form in patients with impaired resorption of cystine.  For most people, these stones form as a result of a genetic condition, called cystinuria, that runs in families.  Therefore, the average cystine stone patient presents at a younger age with multiple stones.

Rare Kidney Stones

There are a number of extremely rare kidney stones (<1%) that are formed in uncommon genetic conditions or by a variety of medications.  These include xanthine, matrix stones and stones made of triamterene, silica, and 2,8-dihyroxyadenine.

BCG for Upper Tract Urothelial Fiction: Reasonable Option or Waste of Time??

Upper tract urothelial cancer (UTUC) refers to cancer of the lining of the kidney (renal pelvis) and ureter.  More information about UTUC can be found in our previous blogs about the Relationship between Upper and Lower Urinary Tract Urothelial Cancer, Causes of UTUC and Chemotherapy for Patients with UTUC. Like urothelial cancers of the bladder, some UTUC can be treated topically with medications like BCG.  This blog will review BCG treatment for patients with UTUC.

Who is a good candidate for BCG treatment?

Similar to urothelial cancers in the bladder, patients with carcinoma in situ (cis) or small, solitary tumors that are completely resected are the best candidates for BCG therapy. Patients with large, bulky, or unresectable tumors are unlikely to benefit from BCG treatment -- as BCG functions to stave off or prevent cancer progression, but is unlikely to have tumors regress.  In addition, patients with positive cytology and no visible tumors, in one or both ureters/kidneys, are eligible for BCG.  In these patients, care should be taken to ensure that the positive cytology did not originate in the bladder and contaminate the upper tract urine sample.  

What is the timing and duration of BCG treatment for UTUC?

In general, patients should wait 2 to 4 weeks following endoscopic resection and for hematuria to resolve prior to initiating BCG treatment.  This will minimize the risk of systemic absorption and side effects from BCG.

Just like bladder treatments, BCG induction is given once per week, every week for six weeks.  Four to six weeks following the last treatment, the patient should undergo cystoscopic evaluation with upper tract evaluations (washings for cytology and/or ureteroscopy with biopsy).  BCG maintenance is an option for UTUC but has not been well studied.

BCG from above or below?

With an ureteral stent in place, fluid can
"reflux" from the bladder up to the kidney.

One of the biggest questions asked by patients and practitioners is how to best get the BCG to the kidney and ureter.  For BCG to work, it must come in contact with the urothelium.  Therefore, BCG must be delivered to the renal pelvis and be allowed to drain down the ureter and into the bladder.  Early studies relied on the placement of ureteral catheters to "stent open" the ureteral orifices and allow BCG given in the bladder to "reflux" up the ureters and into the kidney.  However a number of studies have demonstrated unreliable results with this technique.  In fact, one study using cystograms (contrast dye) to observe reflux in these patients, found that retrograde flow was only observed in 56% of patients and only when a large volume of fluid was instilled into the bladder, a volume larger than usually given in most BCG treatments.[1]

Therefore for reliable delivery of BCG to the upper tract, two methods are employed.

1. ureteral catheters placed through the bladder
2. percutaneous nephrostomy tubes placed through the flank.  

Both of these methods have pros and cons:

Ureteral Catheters

Pros: Does not require anesthesia or sedation for placement.  Stents are removed at the end of each treatment and there is no indwelling hardware.

Cons: Must be placed each week in clinic through a cystoscope.  This is often done without anesthesia, and while safe and well-tolerated, is not the most comfortable procedure to undergo every week for six weeks.    Occasionally fluoroscopy is required to ensure proper placement of the ureteral catheter.  Can be challenging to administer BCG through narrow ureteral stents, limiting the amount of medication that can be given per minute and making treatments longer.

Percutaneous Nephrostomy Tubes

A percutaneous nephrostomy tube is placed through the back, into the kidney,
to reliably instill BCG to the upper tract.

Pros: Can be placed in one setting under anesthesia.  Most reliable method of delivering BCG to the entire upper tract.  Can deliver the medication in a timely fashion (typically instilled over 1 hour).
Cons: Must be  kept in place for the full six weeks of duration and require daily care (flushing with normal saline to keep patent).  Can be uncomfortable, particularly at night if a back or side sleeper.  There is a small risk of tumor seeding (<1%), or growth of cancer along the nephrostomy tube tract.[2]

What are the outcomes for upper tract BCG?

The data regarding BCG for UTUC is heterogeneous in nature, usually involving small patient series with varying tumor types (cis and T1 tumors) and management strategies (stents and percutaneous nephrostomy tubes).  There are no randomized trials comparing BCG to no BCG, comparing management strategies or types of BCG given (some studies give BCG-interferon).  In addition, some patients elect for BCG treatment and other patients are relegated to BCG treatment as they cannot undergo more extensive surgical treatment.

For patients with cis, results from approximately 122 patients are reported in the medical literature.  The overall response rates for BCG treatment in these studies is 86% (ranging from 60-100% in studies) over a mean time period of 15-55 months.  However, response rates refers to "normalization" of urine cytology and 25% of initial responders will recur and 10% will develop metastatic cancer.[3]

For patients with visible tumors who undergo endoscopic resection followed by BCG treatment, the recurrence rate is slightly higher than for those with cis.  In 141 patients, the recurrence rate is approximately 33% (ranging from 11-85%).  Recurrence rates vary with primary tumor grade and are approximately 25% for low-grade tumors and 35% for high-grade cancers.[3]  In the only non-randomized, comparative study evaluating patients who underwent endoscopic resection and received BCG in comparison to those who did not receive BCG, there was no benefit for patients who had high-grade cancer and received BCG.[4]

Summary

• BCG treatment is an option for patients with UTUC who have:
• carcinoma in situ
• a small and/or solitary tumor that is able to be completely resected
• persistent positive cytology with no discernable lesion
• BCG can reliably be given through ureteral catheters or percutaneous nephrostomy tubes
• "reflux" through existing catheters is not a reliable method to deliver BCG
• Response rates vary based on the tumor being treated
• Approximately 85% of patients with cis will have a response to BCG
• 25% may recur, 10% will develop metastases
• Approximately 30% of patients with a resected tumor will recur
• the recurrence rate is higher for patients with high-grade tumors

[1] O. Yossepowitch, D. A. Lifshitz, Y. Dekel, et al., “Assessment of vesicoureteral reflux in patients with self-retaining ureteral stents: implications for upper urinary tract instillation,” The Journal of Urology, vol. 173, no. 3, pp. 890–893, 2005.
[2] Rastinehad AR, Smith AD.  Bacillus Calmette-Guérin for upper tract urothelial cancer: is there a role?  J Endourol. 2009 Apr;23(4):563-8. doi: 10.1089/end.2008.0164. Review.
[3] Ardeshir R. Rastinehad and Arthur D. Smith. Journal of Endourology. April 2009, 23(4): 563-568. doi:10.1089/end.2008.0164.
[4]  Jabbour ME, Smith AD. Primary percutaneous approach to upper urinary tract transitional cell carcinoma. Urol Clin North Am 2000;27:739–750.

Urethral Cancer: Basics of Diagnosis, Staging and Treatment

The urethra is a tube that connects the urinary bladder to the urinary meatus for the removal of fluids from the body.  Urethral cancers grow from the lining of the urethra.  Urethral cancers are rare in both men and women, although they have slightly different epidemiology and etiology depending on sex.  The diagnosis and staging of disease is similar among men and women, however the treatment can be dramatically different.  This blog will review the basics of urethral cancer.

Clinical Presentation

The ratio of male-to-female urethral cancers is believed to be 2:1.[1]  Differences in presentation between men and women are demonstrated in Table 1.

Male Urethral Cancer

Typically presents in middle-aged men in their 40's or later.    Upwards of 50% present with urethral stricture disease and 25% have a history of sexually transmitted infection -- HPV (human papilloma virus) 16 plays a role in the formation of SCC (squamous cell carcinoma) of the urethra.  Greater than 95% of men are symptomatic with symptoms including: urethral bleeding, palpable urethral mass or obstructive voiding.  The symptoms are often slowly progressive, starting with minor symptoms and progressing to major problems -- making early diagnosis a challenge.

Female Urethral Cancer

Urethral cancer is even more rare in women and usually affects women in their 40-50's.  The list of etiologies or related-factors is larger for women and includes: leukoplakia, chronic irritation, caruncles, polyps, parturition, viral infection (HPV) and urethral diverticula (5%) may be related to adenocarcinoma.  Similar to men, >95% of women are symptomatic at presentation with symptoms including: obstructive symptoms (urinary retention is rare in women and malignancy should always be considered in this circumstance), dysuria, urethral bleeding, urinary frequency and/or a palpable urethral mass.

Table 1.

Histology and Pathology 

Urethral cancers are usually urothelial cancers (TCC, transitional cell cancer), SCC or rarely adenocarcinoma.  The prevalence of disease and histology varies by sex and location of tumor.

Male Urethral Cancer

Overall, 80% of urethral cancers in men are SCC with urothelial cancer (15%) and adenocarcinoma (5%) rounding out the remainder of tumors.  Proximal tumors in men are most likely to be urothelial in origin, with rates of SCC increasing with distance from the bulbar urethra (Figure 1).

Figure 1.  Adapted from Cambell-Walsh Urology.

Female Urethral Cancer

In women, 50-70% of urethral cancers are SCC with adenocarcinoma being the second most common tumor type (25%) and urothelial cancer being the most rare (10%).  Histology does not vary by location as it does in men.  Several historical studies indicate that urethral diverticuli have an increased incidence of adenocarcinoma.[2,3]

Figure 2.  Adapted from Cambell-Walsh Urology.

Patterns of Spread

Urethral cancers can be locally invasive and spread into the soft tissues surrounding the urethra.

Male Urethral Cancer

Patterns of lymphatic spread are analagous for male and
female urethral cancer: anterior tumors drain to the
superficial and deep inguinal lymph nodes, posterior
tumors drain to the pelvic lymph nodes.

Local invasion can occur through the spongy tissues of the penis or the corporal bodies.  Tumors that originate in the anterior urethra disseminate through the superificial and deep inguinal lymph nodes, occasionally to the external iliac lymph nodes in the pelvis.  Tumors of the posterior urethra disseminate through the pelvic lymphatic channels, similar to urothelial carcinoma of the bladder.  In men, palpable lymph nodes are present in approximately 20% of patients and always represent metastatic disease (as opposed to penile cancer where these nodes can be inflammatory in nature).

Female Urethral Cancer

Urethral cancers of the female urethra can grow directly into the vulva (skin) of the external genitalia, or when more proximal, invade into the vagina or bladder.  Analagous to male drainage patterns, tumors of the anterior urethra (and labia) drain to the superficial and deep inguinal lymph nodes while tumors of the posterior urethra drain to the external and internal iliac lymph nodes.  Similar to men, most palpable nodes (90%) are malignant.

Diagnosis, Evaluation and Staging

Diagnosis, Evaluation and Staging are identical for men and women and should include:

• Exam under anesthesia
• Cystoscopy
• Bimanual examination
• External genitalia
• Urethra
• Rectum
• Perineum
• Transurethral or needle biopsy
• Cytology is NOT reliable for SCC
• Imaging: CT or MRI
• Abdomen, pelvis to include the genitals and inguinal region.
• Chest radiography

Staging follows the TNM System and prognosis is based on the depth of invasion and presence of lymphatic or distant metastases.

Primary Tumor (T)

TX: cannot be assessed

T0: no evidence of tumor

Ta: Noninvasive papillary, polypoid, or verrucous carcinoma

Tis: carcinoma in situ

T1: Tumor invades subepithelial connective tissue

T2: Tumor invades any of the following: corpus spongiosum (male), prostate (male), periurethral muscle

T3: Tumor invades any of the following: corpus cavernosum (male), beyond prostatic capsule (male), anterior vagina (female), bladder neck

T4: Tumor invades other adjacent organs

Regional Lymph Nodes (N)

NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: Metastasis in a single lymph node, 2 cm or less in greatest dimension

N2: Metastasis in a single lymph node, more than 2 cm but less than 5 cm in greatest dimension; or in multiple nodes, none greater than 5 cm

N3: Metastasis in a lymph node greater than 5 cm in greatest dimension

Distant Metastases (M)

MX: cannot be assessed

M0: no distant metastases

M1: distant metastases

Treatment and Prognosis will be addressed in later blogs.

Summary

• While epidemiology, etiology and treatment of male and female urethral cancer is different, the evaluation and staging are very similar.
• SCC is the most common histology in both men (80%) and women (50-70%).
• 20-33% of patients will have positive lymph nodes at presentation.
• ≥90% of palpable nodes are malignant.
• The anterior urethra drains to inguinal nodes, posterior urethra to pelvic nodes.
• Evaluation should involve:
• Thorough physical examination
• Cystoscopy and biopsy
• Adequate staging by imaging (CT or MRI) +/- chest imaging
• Staging is identical for male and female urethral cancers.

REFERENCES
Sharp, Angermeier.  Surgery of Penile and Urethral Carcinoma.  In: Wein AJ, Kavoussi LR, Partin AW, Peters CA, Novick AC, editors. Campbell-Walsh Urology. 10th ed. Philadelphia: Elsevier; 2012. chapter 35, Pages 934-955.  Eds, Wein, Kavoussi, Novick, Partin and Peters.  

[1] Swartz MA, Porter MP, Lin DW,et al: Incidence of primary urethral carcinoma in the United States. Urology 2006; 68: 1164-1168.
[2] Gheiler EL, Tefilli MV, Tiguert R,et al: Management of primary urethral cancer. Urology 1998; 52: 487-493.
[3] Rajan N, Tucci P, Mallouh C,et al: Carcinoma in female urethral diverticulum: case reports and review of management. J Urol 1993; 150: 1911-1914

Historical Contribution: 1943, Colston, Suitability for Radical Prostatectomy

1943

Carcinoma of the prostate - A study of the percentage or cases suitable for the radical operation J. A. C. Colston Journal of the American Medical Association 1943  122: 781-784

Since Hugh Hampton Young's description of the radical perineal prostatectomy in 1904, Johns Hopkins and the Brady Urological Institute was amongst the world leaders in prostate cancer surgery.  When asked to estimate the proportion of patients undergoing radical prostatectomy in 1942, JAC Colston offered that 5% of patients underwent radical surgery.  When he reviewed the records of 300 patients with prostate cancer treated at Johns Hopkins inthe preceding 5 years, he found that, in fact, 20% underwent radical surgery.  This was a dramatic discrepancy from Colston's own estimate in addition to deviation from practice around the country -- the comparable number from the University of Virginia Hospital was 9% over the same time period.

Colston commented on these statistics:

"I realize that this percentage of cases suitable for the radical operation is probably higher than would be seen in other clinics, but it can be explained by the fact that many patients are referred to this clinic with a diagnosis of early carcinoma for the express purpose of undergoing the radical operation."

Colston was also adamant that the operation was performed in patients "considered suitable for the radical operation with a good prognosis for complete cure."  He laid out the following selection criteria for curative radical prostatectomy:

• organ-confined disease (no locally advanced disease) on clinical examination
• no evidence of metastases on radiography
• serum acid and basic phosphatase are within normal limits
• satisfactory general health ("a fair span of life expectancy")

He also described the palliative operation in cases where cancer extended beyond the tips of the seminal vesicles or invaded the bladder neck.  In both cases, "the patient's subsequent course was much more satisfactory than with any other method of treatment."

Colston also reported the oncologic outcomes:

Interestingly, the only pre-operative prognostic factor was digital rectal examination (DRE).  HH Young was able to dichotomize patients into "good-" or "poor-risk" based on their DRE and this correlated very well with outcome: 41 of 43 patients with a good-risk DRE were alive at last follow-up, while 18 of 26 patients with poor-risk DRE had a cancer recurrence or were dead.

Finally, Colston was also able to report functional outcomes, with good control in most patients.  In addition, a modified suture technique, employed in 1940, resulted in a greater proportion of patients with "good urinary control." 

To read the entire manuscript: follow the link above, visit the Centennial Website or click here.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Journal Spotlight: Randomized Trial of Open and Robotic Radical Cystectomy

Robotic surgery disseminated rapidly over the past decade and is now the most common approach for radical prostatectomy for prostate cancer in the United States.  The dissemination of this technology was fueled by surgeon preference and a number of retrospective and case-series studies that demonstrate improvements in blood loss, convalescence, and hospital stays.[1,2]  However, randomized and/or controlled prospective studies were not performed before robotic surgery took over for prostate cancer.

There is growing interest in robotic surgery for bladder cancer.  The cystectomy (bladder removal) population is often an older, sicker population who undergoes a morbid, radical surgery.  In order to address the utility of robotic surgery for bladder cancer, researchers from MSKCC (Memorial Sloan Kettering Cancer Center) in New York City, reported the results of a small, randomized trial of open versus robotic radical cystectomy for the treatment of bladder cancer.  The results were shared as a Letter to the Editor in the July 24th edition of the NEJM (New England Journal of Medicine).

Bochner BH, Sjoberg DD, Laudone VP.  A Randomized Trial of Robot-Assisted Laparoscopic Radical Cystectomy.  N Engl J Med 2014; 371:389-390July 24, 2014DOI: 10.1056/NEJMc1405213

One-hundred eighteen (118) patients were randomly assigned to undergo open (60) or robotic surgery (58) by a number of experienced surgeons at MSKCC.  The study was designed to detect a difference in complication rates among the two types of surgery.  Given a historic complication rate of radical cystectomy of about 50%,[3] the researchers predicted robotic surgery should improve the complication rate by 20%.  The study was initially designed to enroll over 200 patients, but was stopped early when the complication rates were found to be similar at a pre-determined interim analysis.    

In fact the complication rate was 62% in the robotic group and 66% in the open group at 30 days; high-grade (severe) complications occurred in 22% and 21% respectively.  Important differences in the short-term analysis were:

• decreased blood loss in the robotic group (mean difference, 159 cm3)
• decreased length of surgery in the open group (mean difference, 127 minutes)

This communication was picked up by a number of medical and non-medical publications.  Given the recent skepticism regarding the use of robotic technology, as evidenced an increased reporting of complications in the gynecologic literature, and the increased associated costs with robotic technology,[4,5] a number of sources reflected on this report as a negative study. For instance, the Wall Street Journal ran with the headline, Surgical Robot Fails to Show Advantages in Treating Bladder Cancer, and stated, "This small study may cast further doubt on the benefits of Intuitive Surgical's da Vinci robot."[6]

While this study may not demonstrate a significant benefit to the robotic surgery, it does also not show any detrimental effects, increased complications or worse cancer outcomes for the patients undergoing robotic surgery.  In fact, while the robotic surgery may take longer, the significant lower blood loss may be a worthy trade-off.  In the contemporary radical cystectomy population, a group of patients that often receives chemotherapy before surgery and is subsequently anemic entering the operating room, upwards of 40% of patients will receive a perioperative blood transfusion.  This is especially significant, as recent studies indicate that blood transfusions may be linked to worse cancer outcomes in the bladder cancer population.[7]  Robotic surgery is another tool in the armamentarium of surgeons.  As found in other surgeries, outcomes are often surgeon- and experience-dependent,[8] and this study should not dissuade people from undergoing robotic surgery by an expert surgeon.  The authors and members of this study from MSKCC should be commended for running a successful study comparing a surgical innovation to standard-of-practice and should serve as a model for studies in the future.   

[1] Ficarra V, Cavalleri S, Novara G, Aragona M, Artibani W. Evidence from robot-assisted laparoscopic radical prostatectomy: a systematic review. Eur Urol. 2007;51:45-55; discussion 56. 
[2] Hu JC, Gu X, Lipsitz SR, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA. 2009;302:1557-1564
[3] Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol 2009;55:164-176
[4] Rabin RC. New Concerns on Robotic Surgeries.  The New York Times, September 9, 2013; D4. 
[5] Kolata G. Results unproven, robotic surgery wins converts. The New York Times. February 14, 2010; A1.
[6] Walker, J. Surgical Robot Fails to Show Advantages in Treating Bladder Cancer.  The Wall Street Journal.  July 23, 2014.

[7] Linder BJ, Frank I, Cheville JC, Tollefson MK, Thompson RH, Tarrell RF, Thapa P, Boorjian SA.

The impact of perioperative blood transfusion on cancer recurrence and survival following radical cystectomy. Eur Urol. 2013 May;63(5):839-45. doi: 10.1016/j.eururo.2013.01.004. Epub 2013 Jan 11.

[8] Klein EA, Bianco FJ, Serio AM, Eastham JA, Kattan MW, Pontes JE, Vickers AJ, Scardino PT.Surgeon experience is strongly associated with biochemical recurrence after radical prostatectomy for all preoperative risk categories.J Urol. 2008 Jun;179(6):2212-6; discussion 2216-7. doi: 10.1016/j.juro.2008.01.107. Epub 2008 Apr 18.

The Landscape of Immunotherapy for Urothelial Carcinoma

It is theorized that our bodies create "malignant" cells throughout our lifetime, but our highly evolved and functional immune system prevents these cells from establishing a foothold and becoming a "cancer." Over the last few decades, there have been a number of advances in the understanding of the fundamental regulatory mechanisms governing host immune cell activation and function. With this improved understanding of the immune system came the ability to manipulate immunity to treat diseases – and the field of immunotherapy was born. Immunotherapy refers to the ability to treat diseases (in this case cancers) by inducing, enhancing, or suppressing an immune response. In cancer treatment, immunotherapy encompasses targeted manipulations of the host immune response in order to promote effective immune-mediated tumor destruction. The primary goal of antitumoral immunotherapy is to generate a systemic antigen-specific T-cell response that is capable of destroying the primary tumor, its potential metastases, and if possible the parent tissues that the tumor arises.

Immune Editing Hypothesis

The Immune Editing Hypothesis was put forth by Dunn, Old and Schrieber in 2004 and is described as "The 3 E's" of immunological tumorigenesis.[1] T-cells are an important role in the adaptive immune system and play an important role in mediating anti-tumor immunity. T-cells include CD4 (helper) T-cells and CD8 (killer) T cells. Elimination is conducted through the innate and adaptive immune systems and allows early tumors to be recognized in a productive, proactive way leading to elimination (or destruction) of tumor cells. However, as tumors progress through equilibrium, they acquire genetic and epigenetic alterations that render anti-tumor immune response less effective. Progression can be slowed by an ongoing immune response, however tumors in this phase can no longer by successfully eliminated. Ultimately, tumors escape the immune response through a variety of mechanisms including: down regulation of tumor antigens, induction or expansion of regulatory T cells (Treg) and aberrant expression of T cell co-regulatory molecules that actively inhibit the immune response.

 

Figure 1. Dunn, Old and Schreiber, Immunity 2004

Immunotherapy in Urologic Oncology: 

Intravesical immunotherapy – BCG

While immunotherapy is an emerging and exciting therapeutic option for the treatment of localized and metastatic cancer in multiple tumor types (including melanoma, ovarian, and kidney cancer), it has long played a role in the treatment of urothelial cancers. In fact, BCG (Bacillus Calmette-Guerin) immunotherapy is the mainstay of treatment for non-invasive urothelial malignancies, demonstrating improvements in recurrence, progression and survival in a number of well-established studies. (See our previous blog on Success Rates for Intravesical BCG Treatments for Bladder Cancer) BCG works through both the innate and adaptive immune systems to prevent urothelial cancers from recurring or progressing (See our previous blog on BCG For Bladder Cancer: Why it Works, How it Works).

PD-1 (Marker of Antigen Encounter) and PD-L1 (Marker of Pre-existing Immune Activation) and Urothelial Cancer

A number of cytokines and stimulators exist within the immune system to promote or decrease the immune response to a given stimulus. Negative co-stimulators such like CTLA-4, PD-1 act to inhibit T-cell function and diminish T-cell survival leading to a decrease in immune response and an increase in cancer cell survival. Programmed Death Ligand-1 (PD-L1) and its receptor programmed death-1 (PD-1) are normally used by healthy cells to prevent the immune system from destroying them. Cancer cells can exploit these mechanisms and use PD-L1 and PD-1 to escape the immune system and proliferate. The use of PD-L1 and PD-1 inhibitors have demonstrated incredible response in early studies of patients with advanced kidney cancer (See our blog on Systemic Treatment of Renal Cell Carcinoma: Programmed Death Ligand 1 Inhibitors for more details about the PD-L1/PD-1 Response and Kidney Cancer).
In urothelial cancers, PD-L1 is associated with higher stage and grade, leading to the conclusions that PD-L1 may facilitate local-stage advancement of cancer, attenuate BCG immunotherapy response through altered T-cell response and predict all-cause mortality after radical cystectomy.[2,3]

Figure 2. Inman et. al., Cancer 2007 [2]

In addition, work from Johns Hopkins and other centers have demonstrated that low PD-L1 expression and the presence of CD8+ (killer) T-cells in a tumor specimen may portend a better prognosis – as it indicates that the immune system is functional and fighting off the cancer cells.

Unmet Needs and Future Directions for research and therapy

There are many unanswered questions when considering immunotherapy for urothelial cancer. For instance,

• What are the target antigen(s) when BCG results in cure?
• Besides PD-1 /PD-L1, what are the other mechanisms of escape in urothelial cancer?
• Does chemotherapy promote or prohibit an anti-urothelial cancer immune response?
• Do the epigenetic changes in urothelial cancer render it more or less immunologically sensitive?
• Would combination therapies including chemotherapy, immunotherapy and even radiation therapy results in more durable responses?
  • And what is appropriate timing/sequence of therapy?

To answer these questions and others, researchers at the Brady Urological Institute at Johns Hopkins are developing a genetically engineered mouse model to study combination immunotherapy, chemotherapy and radiation therapy for the treatment of urothelial cancer.

Summary

• Cancer immunotherapy is a rapidly advancing field of both clinical and pre-clinical study, and progress in this area has been especially strong in genitourinary cancers.
• The future of immunotherapy will most likely involve combination approaches, including surgery, immune checkpoint blockade, radiation therapy, conventional chemotherapy.

 
This blog was extracted from "Landscape of Immunotherapy for Urothelial Carcinoma," given by Trinity J. Bivalacqua, MD, PhD; Associate Professor of Urology, Surgery, and Oncology and Director of Urologic Oncology at the Johns Hopkins Medical Institutions and Sidney Kimmel Comprehensive Cancer Center (SKCCC) at the 9^th Annual BCAN (Bladder Cancer Advocacy Network) Think Tank in San Diego, California, August 7-9, 2014.

 

 

 
REFERENCES
[1] Dunn GP1, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004 Aug;21(2):137-48.
[2] Inman BA, Sebo TJ, Frigola X, Dong H, Bergstralh EJ, Frank I, Fradet Y, Lacombe L, Kwon ED. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007 Apr 15;109(8):1499-505.
[3] Boorjian SA, Sheinin Y, Crispen PL, Farmer SA, Lohse CM, Kuntz SM, Leibovich BC, Kwon ED, Frank I. T-cell coregulatory molecule expression in urothelial cell carcinoma: clinicopathologic correlations and association with survival. Clin Cancer Res. 2008 Aug 1;14(15):4800-8. doi: 10.1158/1078-0432.CCR-08-0731.