Friday, October 31, 2014

Retroperitoneal Fibrosis (RPF): Insidious Obstructor of the Ureters

Retroperitoneal fibrosis (RPF) is a benign condition in which the proliferation of fibrotic and inflammatory tissue obstructs retroperitoneal structures including one or both ureters. While RPF is most often managed by nephrologists, it represents a benign proliferation of tissue that may require evaluation and management by urology.  This blog will review the basics of RPF.

Epidemiology and Etiology

In large, cross-sectional studies RPF is a rare disease, presenting in only 0.1 to 1 per 100,000 to 200,000 people.[1, 2] It is more common in men than women (ratio 2-3:1) and typically presents later in life - in the 6th-7th decade - although has been found in both the pediatric and elderly populations.[3, 4] While an inheritance pattern has not been documented, RPF is linked to a number of autoimmune disorders and the HLA-DRB1*03 allele which is linked to multiple sclerosis and rheumatoid arthritis.[5]

The etiology of RPF is not well understood and a number of theories exist. Possible causes include a vasculitis (inflammation) of the small vessels associated with the aorta,[6] immunologic dysregulation that produces an antibody reaction to fibroblasts or a B-cell disorder,[7, 8] or reactive inflammation in response to environmental toxins. As such, a number of medications, chemicals, radiation treatment, local and systemic diseases are associated with the development of RPF (Table).[7, 9] However, a specific etiology is identified in only 30% of RPF cases.[10] Malignancy is associated with 8-10% of RPF cases and should always be considered during initial work-up.[11]  Breast and prostate cancers are historically the cancers that can create a retroperitoneal mass similar to RPF.

Autoimmune Disorders

Medications (cont.)
Ankylosing Spondylitis
Primary Biliary Cirrhosis
Rheumatoid Arthritis
Sclerosing Cholangitis
Retroperitoneal Disease, Trauma or Surgery
Thyroid Disease
Aortic or iliac artery aneurysm; repair thereof
Ascending lymphangitis
Vasculitis, small- or medium-sized vessels
Collagen vascular disease
Henoch-Schonlein purpura with hemorrhage
Methyl methacrylate
Inflammatory response to advanced atherosclerosis
Talcum powder
Ruptured viscera
Retroperitoneal Malignancy
Chronic urinary tract infection
Renal Cell Carcinoma
Urothelial Carcinoma
Any radiation or chemotherapy thereof
β Blockers
Systemic Disease
Inflammatory Bowel Disease
Ergotamine alkaloids

Erdheim-Chester disease


RPF is an insidious, slowly developing disease.  Because it develops so slowsly, symptoms are often imperceivable.  Therefore, patients are often asymptomatic or present in an advanced stage when symptoms of ureteral or vascular obstruction occur.[11] Non-specific signs and symptoms may be related to the underlying etiology. Back, abdominal or flank pain have been described, as have constitutional symptoms (weight loss, anorexia, malaise), low-grade fever, hypertension or lower extremity edema related to chronic vascular obstruction. Blood tests may reveal changes in acute phase reactants (erythrocyte sedimentation rate, c-reactive protein) are elevated in 80-100% of patients and serum creatinine, hypergammaglobulinemia, anemia and autoimmune factors (antinuclear antibody, rheumatoid factor, etc.) may be abnormal but, in general, are not specific for RPF.[7, 12]

Typical findings on imaging include hydronephrosis (swelling of the renal pelvis and ureter), medial deviation of the ureter(s) and a smooth, well-demarcated retroperitoneal mass that surrounds the aorta, inferior vena cava (IVC), iliac vessels and ureters. CT and MRI are excellent modalities for establishing a diagnosis although ultrasound and intravenous pyelography can be used as adjuncts.[11, 13, 14] The retroperitoneal mass may involve one or both sides of the retroperitoneum. If unilateral, the mass may progress to cross the midline and involve bilateral structures (i.e. ureters) over time.

Histology and Pathology

RPF appears as a fibrous, white plaque that encases the major retroperitoneal vessels and structures. Most commonly it involves the aorta, inferior vena cava, major branches of both great vessels and the ureters. The plaque usually extends cranially from the renal hilum to the pelvic brim caudally, although has been demonstrated to extend into the pelvis or mediastinum. Histologically the plaque is composed of fibrotic cellular material (myofibroblasts, type-1 collagen) and a chronic inflammatory infiltrate (lymphocytes, macrophages, plasma cells and eosinophils).[8]


Biopsy is required for the diagnosis of RPF and to exclude malignancy. Core biopsy is preferred to fine needle aspiration; open or laparoscopic biopsy can be performed during ureterolysis if indicated. If histologic findings are consistent with RPF, the first step is to stop all potentially inciting agents or exposures (Table). However, if obstructive uropathy is present, primary therapy should be directed at relieving the obstruction and maintaining renal function prior to initiating a biopsy for diagnosis or medical treatment. Retrograde ureteral stents are often easily passed in patients with RPF, however stents can paradoxically obstruct narrowed ureters associated with RPF. Alternatively, percutaneous nephrostomy tubes offer a reliable drainage method if stenting is not possible or unsuccessful.

Dr. Paul Scheel, MD
Once the urinary obstruction is relieved and a tissue diagnosis is obtained, medical therapy is the preferred initial treatment. Primary treatment is directed at assumed autoimmune and inflammatory etiologies of RPF, initially with a prolonged course of corticosteroids. Using prednisolone or prednisone, a number of dosing regimens are demonstrated to be initially effective in 67-89% of patients with follow-up extending from 15-55 months.[15-17] Azathioprine, colchicines, cyclophosphamide, mycophenolate mofetil and tamoxifen have been used to treat patients with severe RPF or RPF refractory to steroids.[16, 18-21] Importantly, no randomized, prospective studies exist addressing the utility of varying medical treatments or the initial use of medical versus surgical treatment for RPF. Dr. Paul Scheel, MD and Director of the Division of Nephrology at the Johns Hopkins Hospital, is a world expert and leader in the management of RPF. You can visit Dr. Scheel's website by clicking here or on the link below.

In patients refractory or unable to undergo medical treatment, ureterolysis can be performed to relieve ureteral obstruction. Ureterolysis involves completely freeing the ureters from the retroperitoneal mass. It can be performed via an open, laparoscopic or robot-assisted laparoscopic approach.[22, 23]  See the video below for robot-assisted laparoscopic ureterolysis.  Principles of ureterolysis include: biopsy of the fibrotic lesion, initiation of dissection in an area free of disease, avoidance of devascularization of the ureter, lateralization of the ureter, stenting for 6-8 weeks and enclosure within peritoneum or omentum to preserve ureteral vascularity and prevent recurrence.[24] In addition, bilateral ureterolysis should be performed in all cases (even if only a unilateral process is evident during evaluation) as disease can progress to involve both sides and reoperative surgery can be technically challenging. Successful treatment has been reported in 66-100% of surgical series with variable follow-up extending over many years.[22, 25, 26] However, ureterolysis is a complicated, challenging, rare surgery and should only be performed as a last resort. Therefore long-term follow-up is required with serial axial imaging and renal functional studies for an indefinite period of time.

Link: Retroperitoneal Fibrosis at Johns Hopkins Medicine.

This blog is adapted from the Handbook of Urology, Chapter 24: Angiomyolipoma, Oncocytoma and Retroperitoneal Fibrosis, by Phillip M. Pierorazio, MD; Edited by John Kellogg Parsons, John B. Eifler, and Misop Han available from Wiley.


1.    Uibu, T., et al., Asbestos exposure as a risk factor for retroperitoneal fibrosis. Lancet, 2004. 363(9419): p. 1422-6.
2.    Debruyne, F.M., M.J. Bogman, and A.F. Ypma, Retroperitoneal fibrosis in the scrotum. Eur Urol, 1982. 8(1): p. 45-8.
3.    Wu, J., E. Catalano, and D. Coppola, Retroperitoneal fibrosis (Ormond's disease): clinical pathologic study of eight cases. Cancer Control, 2002. 9(5): p. 432-7.
4.    Miller, O.F., et al., Presentation of idiopathic retroperitoneal fibrosis in the pediatric population. J Pediatr Surg, 2003. 38(11): p. 1685-8.
5.    Martorana, D., et al., Chronic periaortitis and HLA-DRB1*03: another clue to an autoimmune origin. Arthritis Rheum, 2006. 55(1): p. 126-30.
6.    Baker, L.R., Auto-allergic periaortitis (idiopathic retroperitoneal fibrosis). BJU Int, 2003. 92(7): p. 663-5.
7.    Vaglio, A., C. Salvarani, and C. Buzio, Retroperitoneal fibrosis. Lancet, 2006. 367(9506): p. 241-51.
8.    Corradi, D., et al., Idiopathic retroperitoneal fibrosis: clinicopathologic features and differential diagnosis. Kidney Int, 2007. 72(6): p. 742-53.
9.    Kavoussi, L.R., et al., eds. Campbell-Walsh Urology. 10 ed. Vol. 2. 2012, Elsevier Saunders: Philadelphia, PA. 1108-1112.
10.    Koep, L. and G.D. Zuidema, The clinical significance of retroperitoneal fibrosis. Surgery, 1977. 81(3): p. 250-7.
11.    Amis, E.S., Jr., Retroperitoneal fibrosis. AJR Am J Roentgenol, 1991. 157(2): p. 321-9.
12.    Monev, S., Idiopathic retroperitoneal fibrosis: prompt diagnosis preserves organ function. Cleve Clin J Med, 2002. 69(2): p. 160-6.
13.    Mulligan, S.A., et al., CT and MR imaging in the evaluation of retroperitoneal fibrosis. J Comput Assist Tomogr, 1989. 13(2): p. 277-81.
14.    Vivas, I., et al., Retroperitoneal fibrosis: typical and atypical manifestations. Br J Radiol, 2000. 73(866): p. 214-22.
15.    Kardar, A.H., et al., Steroid therapy for idiopathic retroperitoneal fibrosis: dose and duration. J Urol, 2002. 168(2): p. 550-5.
16.    van Bommel, E.F., et al., Long-term renal and patient outcome in idiopathic retroperitoneal fibrosis treated with prednisone. Am J Kidney Dis, 2007. 49(5): p. 615-25.
17.    Fry, A.C., et al., Successful use of steroids and ureteric stents in 24 patients with idiopathic retroperitoneal fibrosis: a retrospective study. Nephron Clin Pract, 2008. 108(3): p. c213-20.
18.    Marcolongo, R., et al., Immunosuppressive therapy for idiopathic retroperitoneal fibrosis: a retrospective analysis of 26 cases. Am J Med, 2004. 116(3): p. 194-7.
19.    Swartz, R.D., et al., Idiopathic retroperitoneal fibrosis: a role for mycophenolate mofetil. Clin Nephrol, 2008. 69(4): p. 260-8.
20.    Adler, S., et al., Successful mycophenolate mofetil therapy in nine patients with idiopathic retroperitoneal fibrosis. Rheumatology (Oxford), 2008. 47(10): p. 1535-8.
21.    Scheel, P.J., Jr., et al., Combined prednisone and mycophenolate mofetil treatment for retroperitoneal fibrosis. J Urol, 2007. 178(1): p. 140-3; discussion 143-4.
22.    Duchene, D.A., et al., Multi-institutional survey of laparoscopic ureterolysis for retroperitoneal fibrosis. Urology, 2007. 69(6): p. 1017-21.
23.    Stifelman, M.D., et al., Minimally invasive management of retroperitoneal fibrosis. Urology, 2008. 71(2): p. 201-4.
24.    Varkarakis, I.M. and T.W. Jarrett, Retroperitoneal fibrosis. AUA Update Series, 2005. 24.
25.    Elashry, O.M., et al., Ureterolysis for extrinsic ureteral obstruction: a comparison of laparoscopic and open surgical techniques. J Urol, 1996. 156(4): p. 1403-10.
26.    Alexopoulos, E., et al., Idiopathic retroperitoneal fibrosis: a long-term follow-up study. Eur Urol, 1987. 13(5): p. 313-7.


Hypercalciuria, Calcium in the Urine: Cause or Effect of Stone Disease?

Hypercalciuria, or excessive calcium in the urine, is the most common identifiable cause of kidney stone disease – about 50% of patients who form kidney stones will have hypercalciuria. Calcium is a chemical element used by all living organisms for many cellular processes including transport of molecules across cell membranes, transmission of messages through neurons, and electrical conduction through cardiac cells. In addition, calcium is used by a wide variety of organ-systems including the gastrointestinal, hormonal and skeletal systems – 99% of the body's calcium is stored in bones and teeth.


A careful balance of calcium is required to maintain normal function in the body. In the human, about 30-40% of dietary calcium is absorbed through the intestinal tract and much of the calcium that is not used is excreted through the urine. Other molecules like phosphate, citrate, oxalate, sulfate, and fatty acids bind to (complex) calcium and reduce its availability to be absorbed. Calcitriol (1,25(OH)2D3) is the hormonally active metabolite of Vitamin D and the most potent stimulating signal for calcium absorption by the intestine. Not only does calcitriol promote calcium absorption in the intestine, but it mobilizes osteoclasts – cells that mobilize calcium from the bones of the body – to promote increased calcium availability throughout the body. Parathyroid hormone (PTH) is a hormone released by the parathyroid glands that is turned on in low calcium levels in the body. PTH works with calcitriol to increase calcium levels through a variety of mechanisms, most importantly for this topic, reabsorption by the kidney.



As stated above, hypercalciuria is the most common abnormality found in calcium stone formers. In its normal state, the kidney filters and resorbs about 270mmol of calcium on a daily basis – only 4mmol is is excreted in the urine on average. Definitions of hypercalciuria include:
  • Greater than 200mg urinary calcium/day after adherence to 400mg Ca and 100mg Na diet for one week
  • Greater than 4mg/kg/day or greater than 7mmol/day in men and 6mmol/day in women
In general there are three subtypes of hypercalciuria. These will be discussed below and include:
  • Absorptive hypercalciuria
  • Renal hypercalciuria
  • Resorptive hypercalciuria


Absorptive Hypercalciuria

Absorptive hypercalciuria is defined by increased intestinal absorption of calcium. Patients with absorptive hypercalciuria often have normal fasting urinary calcium (<0.11mg/dL glomerular filtration) as increased absorption matched by increased renal excretion. These patients have normal kidney excretory function, but have increased calcium in the urine because their intestines absorb more calcium. Therefore if given an increased calcium load, they will respond appropriately and have increased calcium excretion.
Technically, absorptive hypercalciuria can be classified into two categories:
  • Type I: urinary calcium remains high despite low calcium diet
  • Type II: urinary calcium normalizes with restricted calcium intake
This classification has no implication for patients and is used for research purposes.


Renal Hypercalciuria

Sometimes called "renal calcium leak," these patients have an increased excretion of calcium without an inciting etiology. It is believed due to impaired renal tubular absorption of calcium, however the actual cause of renal hypercalciuria is unknown. These patients also demonstrate normal serum calcium levels as increased renal excretion is matched by increased intestinal absorption and bone resorption due to normal, compensatory increases in PTH and calcitriol.


Resorptive Hypercalciuria

Resorptive hypercalciuria is caused by primary hyperparathyroidism. In this state, excessive PTH causes elevated serum and urine calcium levels through excessive bone resorption and increased renal synthesis of calcitriol leading to enhanced intestinal absorption of calcium. Less than 5% of patients with resorptive hypercalciuria will develop stone disease. The diagnosis should be suspected in patient with nephrolithiasis and serum calcium levels >10.1mg/dL. Some patients may have normal serum calcium level, therefore repeated measurements of serum calcium may be necessary or measurement of serum ionized calcium may be helpful. It is important to note that thiazide diuretics enhance renal calcium reabsorption and exacerbates hypercalcemia in these patients.



The gold standard test for hypercalciuria is a 24-hour urine study that demonstrates >200mg/day of calcium. Fasting and calium load tests are no longer preferred by most physicians. Instead, the evaluation typically includes:
  • 24-hour urinalysis
  • Stone analysis (most patients present after a stone has been removed or passed)
  • Serum calcium
  • Serum intact parathyroid hormone (iPTH)

Fast and calcium load test:
·         Ca, Na, and oxalate restricted diet for at least 7 days
·         Distilled water (300mL each) taken 12 hours and 9 hours before calcium loading (otherwise fasting)
·         Empty bladder 2 hours before calcium loading and drink 600mL distilled water
·         All urine produced over next 2 hours pooled sample before oral calcium load (fasting urine)
·         1gm oral calcium given using 250mL of liquid synthetic diet (Calcitest) as carrier solution
·         4 hours urine collected as pooled sample (postload urine)
·         Both samples assayed for Ca and Cr – mg Ca /dL glomerular filtrate
·         Normal fasting urinary Ca <0.11mg/dL GF

Patients with absorptive hypercalciuria will have normal serum calcium and low to normal level of iPTH. Renal hypercalciuria will demonstrate normal serum calcium and may have mildly elevated iPTH. Resorptive hypercalciuria will have hypercalcemia (although can have normal serum calcium) and an elevated iPTH. In these patients, two weeks of thiazide diuretic can differentiate from renal hypercalciuria. If a patient does not meet any of these characteristics thay may have idiopathic hypercalciuria.

Type of hypercalciuria
Calcium stones
Urine calcium
Serum PTH
Serum Calcium
Absorptive hypercalciuria
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Renal leak hypercalciuria
Primary hyperparathyroidism


The treatment for hypercalciuria depends on the type of hypercalciuria and involves the use of medications and dietary management of calcium levels.

Medical Management

Thiazide diuretics are widely used to control blood pressure and have secondary effects on urinary metabolites. By inhibiting sodium and chloride transport, they increase calcium reabsorption in proximal tubule and distal tubule of the nephron. This causes extracellular volume depletion with resultant increase in proximal tubular reabsorption of calcium and directly stimulates calcium reabsorption in distal tubule. Patients on thiazide diuretics require potassium supplementation to prevent the side effects of hypokalemia (decreased potassium levels in the blood) and hypocitraturia (decreased citrate in the urine).

For patients with absorptive hypercalciuria, thiazides will reduce calcium excretion but does not directly affect GI calcium absorption. In these patients, their excess calcium is often stored in bone. As the thiazide helps to normalize calcium levels, calcium will leave the bones. When bone density is stabilized, the effect of thiazide becomes attenuated. Thiazide diuretics are the ideal treatment for renal hypercalciuria as they will often correct the "renal leak." In contrast, thiazides are inappropriate for patients with resorptive hypercalciuria as they may exacerbate hypercalcemia.
Sodium cellulose phosphate is a nonabsorbable exchange resin that binds calcium in GI tract and inhibits its absorption. While it appears an ideal medication for patients with absorptive hypercalciuria, Sodium cellulose phosphate is no longer available in U.S. due to significant hazards related to negative calcium balance, magnesium depletion and hyperoxaluria.
For patients with primary hyperparathyroidism (resorptive hypercalciuria), there is no established medical treatment and surgery (parathyroidectomy) is indicated for optimal treatment.

Dietary Management

The general dietary suggestions for patients with stone disease was described in a previous blog entry ( For patients with hypercalciuria, the recommendations include:
  • High fluid intake (goal urine output > 2L/day)
  • Reduced sodium intake (50 mmol sodium chloride daily)
    • Dietary sodium can influence renal calcium excretion
    • Increase of 100mEq/day of sodium will increase urinary calcium by 50mg/day
    • Excess dietary sodium will overwhelm/attenuate hypocalciuric effect of thiazides
  • Reduced animal protein (52 grams per day) intake
  • Normal calcium (30 mmol per day) intake
A common concern is calcium supplementation in the many patients who take supplements, especially postmenopausal women with concern for bone disease.  In patients with hypercalciuria, calcium supplementation can promote worsening hypercalciuria.  If calcium supplementation is suggested, patients should use Calcium Citrate (Citrical).  Calcium Citrate does not significantly change the urinary saturation of CaOx (calcium oxalate) and CaP (calcium phosphate), the two biggest components of most kidney stones.  Therefore, for stone-formers, a 24-hour urine calcium can identify patients at risk for worsening hypercalciuria before starting Calcium Citrate.  If urinary calcium is elevated, they can begin thiazide treatment – which will help with calcium resorption




Tuesday, October 28, 2014

Historical Contribution: 1955, Colston, Partial Nephrectomy on a Solitary Kidney

Colston JAC. Operation for Tumor of a Solitary Kidney. Southern Medical Journal. 1955. 48:12:1280-87.


In 1955, the gold standard treatment for renal neoplasms was radical nephrectomy. Partial nephrectomy had been described and performed for a number of benign conditions since the late 1800's, including calyceal obstruction due to nephrolithiasis (obstruction of a portion of the kidney with a kidney stone), removal of infectious abscess or granuloma in the case of tuberculosis, and removal of renal cysts. Partial nephrectomy for cancerous growths started to gain popularity in the 1930's. In 1950, Vermooten described and advocated for partial nephrectomy based on studies of renal cell carcinoma growth and anatomy.[1] He especially advocated for partial nephrectomy in patients with a solitary kidney. If such patients were "inoperable" they were "otherwise condemned to die" – as either renal cell cancer would take its course or nephrectomy would leave the patient anephric at a time when renal replacement therapy (dialysis) was in its infancy.

At the time of this Historical Contribution by JAC Colston, three cases of partial nephrectomy for tumor were reported in the literature. In this manuscript, Colston added two more cases and successful surgeries. 

The first patient had a right ureteral injury during hysterectomy and subsequent non-functioning kidney due to obstruction. She developed a filling defect in her remaining left kidney and underwent partial nephrectomy through a flank incision for, what ended up being, a papillary urothelial cancer. The patient was disease free four and half years later.

The second patient developed gross, painless hematuria and presented with a tumor of the right kidney and a non-functioning left kidney. Under spinal anesthetic, his non-functioning kidney was explored through a dorsal incision and found to have "no secretory renal tissue." As an aside, the incision of choice for nephrectomy during this time period was often a midline, transabdominal exposure so that the "uninvolved" kidney could be explored prior to nephrectomy to ensure adequate renal function postoperatively. A week after exploration confirming the non-functioning kidney on the left, the patient underwent a partial nephrectomy on the right. Pathology revealed a clear cell adenocarcinoma.

The discussion that follows this manuscript provides some additional commentary and criticism of partial nephrectomy during this time period. Dr. Edwin Alyea from Duke University comments, "Dr. Colston is to be congratulated for his success in this undertaking, and also for bringing this procedure before the profession… Dr. Colston, of course, does not suggest that this patient [in reference to the first patient above] is cured… it is quite probable that it will be true to form and reappear elsewhere in the urinary tract." This is followed by commentary by five other prominent urologists around the country in which they share cases of complex renal pathology or partial nephrectomy. Of interest, is that urothelial and parenchymal tumors were considered in the same spectrum of disease as they both presented with gross hematuria, deformities of the kidney and neither axial imaging nor ureteroscopy were available to distinguish between the two.

Today, nephron-sparing surgery is the gold-standard for all small renal masses to which the operation is technically feasible. This article provides a fascinating look at partial nephrectomy in the 1950's, where the modern indications and techniques were not yet established.

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


To read more about the history of partial nephrectomy, read the excellent article "A HISTORY OF PARTIAL NEPHRECTOMY FOR RENAL TUMORS" by Harry Herr in the March, 2005 edition of the Journal of Urology.


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! 




[1] V. Vermooten. Indications for conservative surgery in certain renal tumors: a study based on the growth pattern of the clear cell carcinoma. J Urol, 64 (1950), p. 200



Monday, October 27, 2014

Journal Spotlight: Surgery vs. Radiation for Prostate Cancer

A number of US-based, observational studies demonstrate that surgery (radical prostatectomy) is superior to radiation therapy for younger patients and those with high-risk prostate cancer. However, most US databases use "representative" data sets, meaning they capture and follow small populations of patients that are believed to be similar to the entire US population. Each data set has its own strengths and weaknesses – and none is perfect. A recent publication by Sookrakumaran and colleagues examined the National Prostate Cancer Registry (NPCR) of Sweden – a comprehensive Swedish database that captures 98% of prostate cancer patients since 1998.

Sooriakumaran P, Nyberg T, Akre O, Haendler L, Heus I, Olsson M, Carlsson S, Roobol MJ, Steineck G, Wiklund P. Comparative effectiveness of radical prostatectomy and radiotherapy in prostate cancer: observational study of mortality outcomes. BMJ. 2014 Feb 26;348:g1502. doi: 10.1136/bmj.g1502.

This study examined over 34,000 men treated with surgery or radiation therapy for prostate cancer followed for up to 15 years. With regard to prostate cancer and total mortality after treatment, the authors found:

  • In the 21,000 men undergoing radical prostatectomy:
    • 339 prostate cancer deaths
    • 1,064 deaths from other causes
  • In the 13,000 men undergoing radiation therapy:
    • 697 prostate cancer deaths
    • 1,127 deaths from other causes
The authors used a number of complex statistical methods and demonstrated that surgery was associated with lower mortality for most patients, specifically those at the greatest risk from death from prostate cancer (young men with intermediate- or high-risk prostate cancer). Men with low-risk disease, especially older men, who have a low-risk of death from prostate cancer had no difference in survival after either treatment. The authors went to great statistical efforts to control for variables that could alter the outcomes of the analysis. Specifically, radiation therapy was given with lower doses early in the experience of the database – a sensitivity analysis demonstrated that radiation dose should not affect outcomes.

From Sooriakumaran etal. 

A number of prospective, randomized studies are underway to examine the question of surgery vs. radiation therapy for prostate cancer. However, due to the slow-progression rate of prostate cancer, results are at least 10 years away. These include the ProtecT Study in the United Kingdom and the SPCG-15 (Surgery versus Radiotherapy for Locally Advanced Prostate Cancer) Study.

Friday, October 24, 2014

Immunotherapy for the Treatment of Bladder Cancer


A 57-year-old man presented with a 30-pack year smoking history and high grade non-invasive bladder cancer. He initially underwent resection followed by a course of BCG, but developed a low-grade recurrence. He required further resection and a subsequent course of BCG + Interferon. He was kept on surveillance, but is again found to have T1 high-grade bladder cancer. He is strongly opposed to radical cystectomy and seeks alternative "bladder-sparing" options. Molecular analysis of his tumor was performed and showed FGFR3 mutation.


One of the most challenging dilemmas in urologic oncology is the patient with BCG-refractory and recurrent high-grade, non-muscle invasive urothelial cancer of the bladder. These patients are at an extremely high risk of progression to muscle-invasive, dangerous or fatal disease; however, justifying a major extirpative surgery is difficult when no invasive disease is present. This blog will review immunotherapy as a cutting edge therapy for such patients.

At initial diagnosis of bladder cancer, 75% of disease is locally confined, while 25% has advanced to regional/metastatic disease.[1] Of localized disease, 70% is found to be non-muscle invasive.[2] Indeed, molecular analyses of numerous bladder tumors demonstrate that there are two alternative processes that occur in the development of bladder cancer (Figure 1). A hyperplastic process that is associated with mutations in HRAS and FGFR3 genes can occur, leading to a low-grade non-invasive papillary tumor phenotype. Alternatively, a dysplastic process that is associated with loss of tumor suppressors p53 and RB can also occur, leading to an invasive tumor phenotype.[3]

Figure 1. Diagram of alternative processes occurring in urothelial carcinoma. Xu WR. 2005.[3]
Studies looking specifically at FGFR3 mutation status in tumor tissue show that FGFR3 is commonly mutated in non-invasive bladder cancer and also associated with a high level of recurrence.[4] Indeed, mutation occurs more frequently in lower stage and lower grade tumors (Figure 2).

Figure 2. FGFR3 is mutated more frequently in lower stage and grade tumors. Knowles. 2007.[4]

FGFR3 belongs to the Fibroblast Growth Factor Receptor family and includes 18 different proteins (ligands) and 4 different FGF receptors that control functions such as cell differentiation, proliferation, angiogenesis, and invasion.[5] There is a wealth of pre-clinical and laboratory literature that suggests FGFR3 may be an effective therapeutic target in bladder cancer. For instance, a mouse model of bladder tumors demonstrated an 84% reduction in UM-UC1 (a tumor cell line that overexpresses FGFR3), shrinking tumor size and reduced cell proliferation on microscopic examination (Figure 3).[6]

Figure 3. R3Mab, a monoclonal antibody against FGFR3, resulted in smaller UM-UC1 (over-expresses wt FGFR3) tumor xenografts and decreased cell proliferation compared to control IgG in an orthotopic in vivo mouse model. The cell line was transfected with a luciferase plasmid for the bioluminescence scan. Gust et al. 2013.[6]

Dovitinib is an oral medication, classified as a multi-kinase inhibitor with activity against a number of target molecules including FGFR1-4, VEGFR, PDGFR, FLT3, and c-KIT.[7] Laboratory evidence presented by Milowsky et al. demonstrated that Dovitinib could reduce tumor markers and tumor size in a dose-dependent manner, and was superior to tyrosine kinase inhibitors, sorafenib and sunitinib, at inhibiting growth.[8]

There is also clinical data to support the use of Dovitinib. Andre et al. analyzed the effectiveness of Dovitinib in treating women with metastatic breast cancer with FGFR1 mutation. This trial was in a patient population with very advanced disease – 78% of women had liver metastases and had received prior treatment with up to 3 hormone and chemotherapeutic agents or up to 3 chemotherapeutic agents, depending on their hormone receptor status. Nevertheless, there were a greater proportion of the patients treated with Dovitinib that had a partial clinical response or stable disease at ≥ 24 weeks follow up. Furthermore, tumors with large amounts of FGFR1 (amplification greater than 6 copies) showed a 20.2% reduction in tumor burden from baseline compared to tumors with less than 6 copies that had a mean 8.3% increase from baseline. The authors also showed in a waterfall plot that patients with FGF pathway mutation trended toward reduction in tumor burden as compared to increase in tumor burden in those that did not have FGF amplification (Figure 4).[9] Because of its effects against multiple tyrosine kinases, toxicity is a concern for Dovitinib and safety data from the trial showed that nausea, vomiting, diarrhea, and asthenia were common complications. Less common, but more serious complications included: hypertriglyceridemia, pulmonary embolism, and myocardial infarction.

Figure 4. Dovitinib was more effective in reducing tumor burden in tumors with FGF pathway amplification.
From Andre et al 2013.[9]
A recent Dovitinib Trial has opened at Johns Hopkins for the treatment of non-muscle invasive, recurrent bladder cancer.  The trial was designed by Dr. Noah M. Hahn, MD, Associate Professor of Oncology and Urology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and is open to patients with histologically confirmed low stage disease (Ta, T1, or Tis), FGFR3 mutation, and documented BCG-refractory disease (evidence of disease after two courses of BCG). Patients are not allowed into the study if they have muscle-invasive disease, non-resectable locally advanced disease, or concurrent upper urinary tract non-invasive urothelial carcinoma. Patients enrolled in the trial will receive Dovitinib 500 mg orally for 5 days on and 2 days off. Cystoscopy with tumor and bladder biopsy, and urine cytology will occur every 3 months. The primary end point of the study is the 6-month complete response rate (no evidence of disease). Other outcomes of interest include the 1-year relapse free survival rate, the rate of progression to invasive bladder cancer, and the 3 and 6-month partial response rates (evidence of disease but lower stage than initially diagnosed). Further information can be found on GU12-157.[10]

In conclusion, FGFR3 is a potential therapeutic target in non-invasive urothelial carcinoma and Dovitinib is a multi-kinase inhibitor that may be effective for treatment in this setting. The Dovitinib trial at Hopkins is currently enrolling patients and offers bladder sparing treatment for patients with non-invasive BCG-refractory disease and FGFR3 mutation.

This blog was written by Matthew Lee, a medical student at Columbia University, College of Physicians & Surgeons in New York, New York. Matthew recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "A Phase II Clinical Trial of Dovitinib in BCG Refractory Bladder Cancer" from which this blog is inspired. Matthew is looking forward to a career in urology.

[1] Konety BR, Carroll PR. Urothelial Carcinoma: Cancers of the Bladder, Ureter, & Renal Pelvis. Smith’s Urology. Ch 21. 18 ed. 2013
[2] Pandith AA, Shah ZA, Siddiqui MA. Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer. Urologic Oncology: Seminars and Original Investigations. 2013; 31: 398-406. 
[3] Wu XR. Urothelial tumorigenesis: a tale of divergent pathways. Nature Reviews Cancer. 2005; 5:713-25.
[4] Knowles MA. Role of FGFR3 in urothelial carcinoma: biomarker and potential therapeutic target. World J Urology. 2007; 25: 581-593.
[5] Katoh M, Nakagama H. FGF Receptors: Cancer Biology and Therapeutics. Medicinal Research Reviews. 2014; 34(2):280-300.
[6] Gust KM, McConkey DK, Awrey S. et al. Fibroblast growth factor receptor 3 is a rational therapeutic target in bladder cancer. Mol Cancer Ther. 2013; 12: 1245-1254.
[7] Chase A, Grand FH, Cross NCP. Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome. Blood. 2007; 110: 3729-3734.
[8] Milowsky MI. Carlson GL, Shi MM, Urbanowitz G.  Zhang Y.  Sternbeerg CN. A multicenter, open-label phase II trial of dovitinib (TKI258) in advanced urothelial carcinoma patients with either mutated or wild-type FGFR3. Poster presented at ASCO Annual Meeting 2011. J clin ONcol 29: 2011 (suppl; abstr TPS186).
[9] Andre F, Bachelot T, Campone M, et al. Targeting FGFR with Dovitinib (TKI258): Preclinical and Clinical data in Breast Cancer. Clin Cancer Res. 2013; 19: 3693-3702.
[10] Hahn N. Dovitinib in BCG Refractory Urothelial Carcinoma with FGFR3 mutation or overexpression. NCT01732107.