Historical Contribution: 1923, Young & Hill,Mercurochrome & Gentian Violet

1923
HH Young, Hill JA. The Treatment of Septicemia and Local Infections By Intravenous Injection of Mercurochrome 220 Soluble and of Gentian Violet. JAMA. 1924;82:669-75.


 
In 1919, Hugh Hampton Young published the first report of mercurochrome-220 to sterilize the bladder in the Journal of the American Medical Association (JAMA) (click here for link to Historical Contribution: 1919). Four years later, he writes the follow-up manuscript demonstrating the effectiveness of mercurochrome in the treatment of a variety of bacterial infections. In addition, he describes the use of gentian violet, a potent antimicrobial for gram-positive staphylococci. After proving intravenous instillation of gentian violet in rabbits is safe – Young endeavors on human treatment with the medication.

In total, Young presents 12 cases treated and cured with mercurochrome – the first one in 1922. In patients 1-7, Young meticulously details the tenuous clinical course of patients afflicted with septicemia, retroperitoneal and abdominal abscesses, kidney and bladder infections treated by intravenous mercurochrome.

In patients 8-12, Young describes the use of intravenous gentian violet. The first intravenous dose of gentian violet was given July 12, 1923 to a patient with staphylococcus aureus urinary tract infection related to a ureteral calculus. The remaining cases demonstrated cure of systemic staphylococcal infections including those stemming from complications of diabetes, osteomyelitis, urinary system infections. Importantly, gentian violet cleared the source of infection, improved systemic infection, and cleared sequealae of the systemic infection (i.e. abscesses).
In his typical fashion, Young took meticulous notes regarding the clinical course and laboratory values associated with each patient. Not only was the defervescence and normalization of vital signs in septic patients impressive, but the hourly documentation of blood and urine cultures demonstrating true sterilization of the infection.

 
To summarize, in the early 1900's, septicemia was almost universally fatal and mercurochrome ushered in a new era of antimicrobial treatment and hope for the treatment of infectious disease. Patients in this series were described as "desperate cases" – in which experimental antimicrobial treatments were justified. Young was extremely pleased with the results; he describes the sure and sterilization of the blood by intravenous mercurochrome "miraculous" and goes on to say,

"In these cases we have the first demonstration that gentian violet may be used intravenously to combat general septicemia or local infections, and with remarkable success in the case of gram-positive staphylococci. Coupled with the equally amazing results obtained by mercurochrome, these cases represent a splendid therapeutic achievement, and one is tempted to soar into realms of fancy and see a great variety of infectious processes treated and cured intravenously;"

Read more about mercurochrome in publications by Hugh Hampton Young by clicking on the following links:
Historical Contribution, 1919
Historical Contribution, 1925

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! 

Oncocytoma: A Benign Kidney Tumor Often Confused for Cancer

Upwards of 15-20% of kidney tumors may be benign lesions. While physicians and surgeons can use patient information, radiographic imaging and biopsy to provide information, the definitive diagnosis of cancer or benign tumor is established only after the tumor has been removed. For instance, smaller tumors, female sex and age are associated with benign tumors - younger women are nearly twice as likely as age-matched men to have benign masses.[1-5] While certain characteristics are indicative of benign tumors (i.e. fat always indicates an angiomyolipoma), many other benign tumors – like oncocytoma – can appear similar to renal cell carcinoma (RCC) on CT scan and biopsy.

This blog will review oncocytoma, one of the most common benign tumors of the kidney.

Epidemiology and Etiology

Renal oncocytoma is one of the most common of benign renal masses, accounting for 3-7% of kidney tumors.[6] Oncocytomas appear as enhancing renal masses and are often indistinguishable from clear-cell RCC on CT scans (see Diagnosis below). Both oncocytomas and clear-cell RCC pick up contrast material and enhance brightly. However, oncocytoma is a distinct entity from RCC with unique cell of origin and cytogenetic abnormalities.[7-8]

Oncocytomas are more common in older patients with small, incidentally discovered renal masses. [4,9] Generally, they are more common in men than women (2:1 ratio), present in the 4th to 6th decade of life and can present bilaterally, multifocally or recur in 6-13% of cases.[10] Patients with the rare, Birt-Hogg-Dubé, genetic syndrome can present with oncocytomatosis – the presence of multiple oncocytomas in both kidneys. [11] Oncocytomas are benign tumors and rare case reports of metastatic oncocytoma represent either malignant degeneration, coexistence of RCC or pseudometastases (not really metastatic disease).[12]

Diagnosis

In general, oncocytoma appear similar to RCC on imaging. However, a number of characteristic radiographic findings are common in oncocytoma:

• On CT scan, bright, rapidly-enhancing pattern and a central stellate scar [13]
• On angiography, a spoke wheel pattern of feeding arteries may be present
• On MRI, a well-defined capsule, central stellate scar, and distinctive pattern on T1 and T2 images may indicate oncocytoma.[14,15]

The similar appearance of clear-cell RCC and oncocytoma on contrast-enhanced CT scan.

The Houndsfield Unit (HU) -based enhancement patterns for clear-cell RCC and oncocytoma are overlapping on CT scan. [13]

Renal biopsy has a limited role in the diagnosis of oncocytoma, particularly because it can be difficult to distinguish from chromophobe RCC (see our blog entry on Renal Cell Carcinoma: Implications of Histology for more information about chromophobe RCC), the eosinophilic-variant of clear-cell RCC (a rare and potentially aggressive form of kidney cancer) and may be co-exist with RCC in 7-32% of cases. However, surgical series indicate that if oncocytoma is present with RCC in the same tumor, the tumor is often low-grade and indolent (benign-behaving).[16]

Histology and Pathology

Oncocytomas appear grossly as tan, homogenous tumors with a distinct border (composed of a well-formed pseudocapsule) and typically have a central stellate scar. Microscopically, cells are derived from distal tubules, are rounded and highly-eosinophlic (pink) due to an abundance of mitochondria (the energy producing portion of the cell). As stated above, it can extremely difficult to distinguish oncocytoma from chromophobe RCC or the eosinophilic-variant of clear-cell RCC under the microscope. Cells are typically arranged in a nested pattern and can demonstrate perinephric extension, pleomorphism (variability in size and shape), prominent nucleoli and atypia, making the distinction between RCC difficult.[17,18] On a percutaneous renal biopsy, where only a portion of tumor is present and cellular architecture is incomplete, distinguishing oncocytoma from RCC can be extremely challenging.

From pathologyatlas.com

To distinguish ococytoma from RCC, a number of features can be examined. Chromosomal abnormalities associated with RCC are not present in oncocytoma, and oncocytoma will commonly present with loss of chromosome 1p, loss of Y- or 14q- and rearrangements of 11q13. [7,8] Hale's colloidal iron stain has traditionally been used to identify oncoctyoma, however can have nonspecific staining patterns leading to difficult interpretation.[19] One of the distinguishing cellular features of oncocytoma is uniform, round mitochondria with lamellar cristae – in chromphobe RCC, mitochondria are variable in size and shape with tubulocystic cristae; and in eosinophilic-variant of clear-cell RCC, mitochondria are pleomorphic and have attenuated cristae.[20] Researchers at Johns Hopkins are taking advantage of differences in mitochondria among oncocytoma and RCC to come up with a better, preoperative diagnostic test to distinguish oncocytoma before a sending a patient to surgery.

Electron micropscopy of oncocytoma with uniform, round mitochondria (left) and chromophobe RCC with the pale area around the nucleus is predominantly occupied by microvesicles and irregular mitochondria (right).[20]

Management

Most often oncocytoma are clinically assumed to be RCC and have the same management strategies available including active surveillance, radical nephrectomy (for large tumors of uncertain etiology) and nephron-sparing surgeries including partial nephrectomy and thermal ablation. Oncocytomas under active surveillance can demonstrate rapid growth and are often the fastest growing tumors in active surveillance studies! Therefore, growth rate is not able to distinguish oncocytoma from RCC during periods of AS.[21,22] When the diagnosis of oncocytoma is known or highly-suspected, nephron-sparing approaches should be employed due to the benign nature of these lesions. At Johns Hopkins, partial nephrectomy is preferred to thermal ablation as a definitive diagnosis can be made from analysis of the tumor rather than biopsy specimens.

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. Kutikov A, Fossett LK, Ramchandani P, et al.: Incidence of benign pathologic findings at partial nephrectomy for solitary renal mass presumed to be renal cell carcinoma on preoperative imaging. Urology 2006; 68(4): 737-40.
2. Kouba E, Smith A, McRackan D, Wallen EM, Pruthi RS: Watchful waiting for solid renal masses: insight into the natural history and results of delayed intervention. J Urol 2007; 177(2): 466-70; discussion 470.
3. Pierorazio PM, Murphy AM, Benson MC, McKiernan JM: Gender discrepancies in the diagnosis of renal cortical tumors. World J Urol 2007; 25(1): 81-5.
4. Cao Y, Paner GP, Perry KT, Flanigan RC, Campbell SC, Picken MM: Renal neoplasms in younger adults: analysis of 112 tumors from a single institution according to the new 2004 World Health Organization classification and 2002 American Joint Committee on Cancer Staging System. Arch Pathol Lab Med 2005; 129(4): 487-91.
5. Snyder ME, Bach A, Kattan MW, Raj GV, Reuter VE, Russo P: Incidence of benign lesions for clinically localized renal masses smaller than 7 cm in radiological diameter: influence of sex. J Urol 2006; 176(6 Pt 1): 2391-5; discussion 2395-6.
6. Morra MN, Das S: Renal oncocytoma: a review of histogenesis, histopathology, diagnosis and treatment. J Urol 1993; 150(2 Pt 1): 295-302.
7. Lindgren V, Paner GP, Omeroglu A, et al.: Cytogenetic analysis of a series of 13 renal oncocytomas. J Urol 2004; 171(2 Pt 1): 602-4.
8. Paner GP, Lindgren V, Jacobson K, et al.: High incidence of chromosome 1 abnormalities in a series of 27 renal oncocytomas: cytogenetic and fluorescence in situ hybridization studies. Arch Pathol Lab Med 2007; 131(1): 81-5.
9. Skolarus TA, Serrano MF, Berger DA, et al.: The distribution of histological subtypes of renal tumors by decade of life using the 2004 WHO classification. J Urol 2008; 179(2): 439-43; discussion 443-4.
10. Minor LD, Picken MM, Campbell SC: Benign renal tumors. AUA Update 2003; 22: 170-175.
11. Al-Saleem T, Cairns P, Dulaimi EA, Feder M, Testa JR, Uzzo RG: The genetics of renal oncocytosis: a possible model for neoplastic progression. Cancer Genet Cytogenet 2004; 152(1): 23-8.
12. Oxley JD, Sullivan J, Mitchelmore A, Gillatt DA: Metastatic renal oncocytoma. J Clin Pathol 2007; 60(6): 720-2.
13. Pierorazio PM1, Hyams ES, Tsai S, Feng Z, Trock BJ, Mullins JK, Johnson PT, Fishman EK, Allaf ME. Multiphasic enhancement patterns of small renal masses (≤4 cm) on preoperative computed tomography: utility for distinguishing subtypes of renal cell carcinoma, angiomyolipoma, and oncocytoma. Urology. 2013 Jun;81(6):1265-71. doi: 10.1016/j.urology.2012.12.049. Epub 2013 Apr 17.
14. Licht MR: Renal adenoma and oncocytoma. Semin Urol Oncol 1995; 13(4): 262-6.
15. Harmon WJ, King BF, Lieber MM: Renal oncocytoma: magnetic resonance imaging characteristics. J Urol 1996; 155(3): 863-7.
16. Ginzburg S, Uzzo R, Al-Saleem T, Dulaimi E, Walton J, Corcoran A, Plimack E, Mehrazin R, Tomaszewski J, Viterbo R, Chen DY, Greenberg R, Smaldone M, Kutikov A. Coexisting hybrid malignancy in a solitary sporadic solid benign renal mass: implications for treating patients following renal biopsy. J Urol. 2014 Feb;191(2):296-300. doi: 10.1016/j.juro.2013.07.059. Epub 2013 Jul 27.
17. Amin MB, Crotty TB, Tickoo SK, Farrow GM: Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol 1997; 21(1): 1-12.
18. Perez-Ordonez B, Hamed G, Campbell S, et al.: Renal oncocytoma: a clinicopathologic study of 70 cases. Am J Surg Pathol 1997; 21(8): 871-83.
19. Leroy X, Moukassa D, Copin MC, Saint F, Mazeman E, Gosselin B: Utility of cytokeratin 7 for distinguishing chromophobe renal cell carcinoma from renal oncocytoma. Eur Urol 2000; 37(4): 484-7.
20. Tickoo SK, Lee MW, Eble JN, Amin M, Christopherson T, Zarbo RJ, Amin MB. Ultrastructural observations on mitochondria and microvesicles in renal oncocytoma, chromophobe renal cell carcinoma, and eosinophilic variant of conventional (clear cell) renal cell carcinoma. Am J Surg Pathol. 2000 Sep;24(9):1247-56.
21. Kawaguchi S, Fernandes KA, Finelli A, Robinette M, Fleshner N, Jewett MA: Most renal oncocytomas appear to grow: observations of tumor kinetics with active surveillance. J Urol 2011; 186(4): 1218-22.
22. Siu W, Hafez KS, Johnston WK, 3rd, Wolf JS, Jr.: Growth rates of renal cell carcinoma and oncocytoma under surveillance are similar. Urol Oncol 2007; 25(2): 115-9.

Bladder Preservation Strategies in the Treatment of Muscle-Invasive Bladder Cancer

It is estimated that in 2014, there will be 74,690 new cases bladder cancer and 15,580 deaths secondary to bladder cancer.1 Approximately 20-30% of patients with bladder cancer present with muscle-invasive bladder cancer (MIBC). The standard of care for MIBC is a radical cystectomy with removal of the pelvic lymph nodes, with some patients undergoing chemotherapy prior to surgery (neoadjuvant chemotherapy). While radical cystectomy is the preferred treatment option, it has significant morbidity and implications on quality of life.2,3 Therefore, bladder preservation therapies for MIBC have been developed, and may be an option for a select group of patients.4

Bladder preservation strategies include combination therapies as well as single modality therapies. Trimodal therapy, consisting of an aggressive transurethral resection of bladder tumor followed by concurrent chemotherapy and radiation therapy, is the most strongly supported and accepted bladder preservation option. In a recent systematic review, the 5-year cancer specific survival in medically operable patients undergoing trimodal therapy was 50-82%.5 These numbers are comparable to large radical cystectomy series. While there are no randomized trials comparing trimodal therapy to radical cystectomy, there is a growing body of accumulated data suggesting that trimodal therapy is a reasonable treatment option in well-selected patients.

While trimodal therapy is the most accepted option for bladder preservation, for the remainder of this post, we will discuss the role of each individual modality (transurethral resection, chemotherapy, and radiotherapy) in trimodal therapy, and outline some non-traditional approaches to bladder preservation.

Transurethral resection of bladder tumor

Transurethral monotherapy involves excising all visible tumor with deep resection. In highly selected patients, Dr. Harry Herr presented a series of 151 patients with MIBC that underwent an aggressive transurethral resection of bladder tumor with 10 years of follow-up.6 Of these patients, 99 underwent transurethral resection alone and 52 underwent radical cystectomy. There was no significant difference in survival between these groups, and overall, 57% of patients in this study survived more than 10 years with a functioning bladder. While these results are noteworthy, limited data overall supporting radical transurethral resection as monotherapy. Furthermore, there is a lifelong risk of developing recurrent invasive tumor in retained bladder: 42% of patients in this study underwent salvage radical cystectomy. The general consensus is that transurethral resection alone provides inadequate cancer control with high rate of recurrence and progression.

Chemotherapy

While the primary role for chemotherapy in the treatment of MIBC is neoadjuvant chemotherapy, there are circumstances where a patient will have no evidence of tumor following chemotherapy, and will subsequently refuse a cystectomy. Small series have described this scenario with good outcomes. In a recent retrospective review of 32 patients with muscle-invasive bladder cancer that had a clinical complete response to neoadjuvant chemotherapy, 25 patients refused to undergo an immediate cystectomy.7 Of the 25 patients that refused immediate cystectomy, 7 patients underwent delayed cystectomy for relapse and 18 patients successfully maintained their bladders. There was no difference in the cancer specific survival between patients that underwent immediate cystectomy and patients that opted for a bladder preservation strategy. We see that in select patients that achieve a complete response to neoadjuvant chemotherapy, bladder preservation may be achieved. However, at this point, it is difficult to determine who will have a response to neoadjuvant chemotherapy, and of those, who will be able to durably maintain their bladders.

Radiation Therapy

A multicentered randomized phase 3 trial examined the role of radiation alone versus radiation with chemotherapy in the treatment of MIBC.8 The authors found that the locoregional and invasive disease free survival was significantly better in the patients that underwent chemoradiation therapy as opposed to radiation alone. Furthermore, there was no increased toxicity with the addition of chemotherapy. The authors did not compare these modalities to patients undergoing cystectomy. Overall, when examining bladder preservation options, there is no role for radiation therapy alone, as concurrent chemoradiation is more effective.

SUMMARY

In conclusion, there are multiple options for bladder preservation. There are large trials reporting outcomes for trimodal therapy and small series for single modality treatments. From these experiences, we see that bladder preservation strategies can lead to acceptable outcomes, and may be considered a reasonable treatment option in select patients. Bladder preservation is not an option for all patients with MIBC, and patient selection is of paramount importance. Furthermore, it is essential to recognize that in these studies, only select patients were included. Bladder preservation is a treatment approach under investigation, and prospective trials comparing trimodal therapy and single modality bladder preservation options to radical cystectomy are needed to better define their role in the treatment of MIBC.

This blog was written by Alexa Meyer, Medical Student at Columbia University College of Physicians & Surgeons in New York, New York.  Alexa recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Trimodal Therapy for Bladder Cancer" from which this blog is inspired. Alexa is looking forward to a career in urology.






1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.
2. Aghazadeh MA, Barocas DA, Salem S, et al. Determining factors for hospital discharge status after radical cystectomy in a large contemporary cohort. J Urol 2011;185:85-9.
3. Goodney PP, Stukel TA, Lucas FL, Finlayson EV, Birkmeyer JD. Hospital volume, length of stay, and readmission rates in high-risk surgery. Ann Surg 2003;238:161-7.
4. Smith ZL, Christodouleas JP, Keefe SM, Malkowicz SB, Guzzo TJ. Bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC): a review of the literature and a practical approach to therapy. BJU Int 2013;112:13-25.
5. Ploussard G, Daneshmand S, Efstathiou JA, et al. Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review. Eur Urol 2014;66:120-37.
6. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 2001;19:89-93.
7. Meyer A, Ghandour R, Bergman A, et al. The natural history of clinically complete responders to neoadjuvant chemotherapy for urothelial carcinoma of the bladder. J Urol 2014;192:696-701.
8. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477-88.

Active Surveillance for Kidney Cancer: Questions and Details

Active surveillance is the least invasive option for managing a kidney tumor. At Johns Hopkins, "active surveillance" is preferred to terms like "observation" or "watchful waiting," as these indicate a passive approach where we wait for something bad to happen. Active surveillance is, by definition, an involved process where patients and tumors are watched very closely, where tumor size and growth characteristics are monitored, and the need for treatment is reassessed on a regular basis.

Why active surveillance?

Kidney tumors are biologically heterogeneous – this means they come in all shapes, sizes and behaviors. Some are completely benign tumors, some are cancers that behave like benign tumors and some can be very aggressive. Most small kidney tumors (less than or equal to 4cm) are either benign or behave like benign tumors. The bigger a tumor gets, the more likely it is a dangerous cancer and conversely, the smaller a tumor is, the more likely it is benign or behaves in a benign fashion. While Hopkins is an expert center for kidney surgery, not all patients need to undergo surgery – especially if they have a benign or benign-behaving tumor.

Who is a good patient for active surveillance?

Several patient characteristics make active surveillance an attractive option:

• Tumor size: the smaller the tumor, the higher likelihood of having a benign or benign-behaving cancer.
• Tumors less than or equal to 4cm can safely undergo active surveillance, although the risk of cancer spreading from a tumor is smaller for tumors less than 3cm and is <1% for tumors <2cm. 
• Older patients who are medically fragile: Since the risk that the small kidney tumor spreads is low, in patients with a short life expectancy (<10years) a discussion regarding active surveillance may be prudent. Many of these patients die WITH the kidney tumor rather than OF the kidney tumor.
• Patients with poor kidney function: Since any intervention on the kidney can cause further deterioration of kidney function, these patients may be better off selecting active surveillance. In some patients, further decline in kidney function puts the patient at risk of needing dialysis. Dialysis, while life-saving, may be associated with poor outcomes and a low quality of life. Ask your doctor about your creatinine level which is an indicator of kidney function (normal is around 1.0 mg/dl).
• Patients with hereditary forms of kidney cancer: This includes patients with Von-Hippel-Lindau (VHL), Birt-Hogg-Dube (BHD), or other conditions in which patients are at risk of having multiple and recurrent tumors in both kidneys. These tumors are typically placed on active surveillance until they reach 3cm or larger.
• Patients who are experiencing or recovering from an active serious medical problem: 
• Active, serious medical issues can include patients with heart failure and/or significant vascular disease. These patients are excellent candidates for active surveillance as these chronic medical conditions increase the risks of surgery.
• An example of a recovering medical issue is patients who have drug eluting heart stents or patients who temporarily need to be on a blood thinner like warfarin (Coumadin). Kidney surgery/intervention can result in severe bleeding in these patients and thus a period of active surveillance until they can come off the blood thinners may be helpful to avoid a potential serious complication. A period of active surveillance until things stabilize should be entertained.
• Patients who are extremely anxious about having surgery or do not wish to have treatment: While urologists at Johns Hopkins are expert surgeons who perform a large number and variety of kidney surgeries safely, these surgeries are not without risks. Surgery is not for everyone. 

What does active surveillance involve?

The initial evaluation includes a complete history and consideration of other health risks, a thorough staging evaluation (imaging of the chest, abdomen, and pelvis) to make sure the tumor is confined to the kidney, blood work and urine tests to evaluate kidney function. After the initial evaluation, repeat imaging is recommended every six months for the first two years, and annually thereafter. However, active surveillance is often tailored to the patient and the protocol can be customized for each patient.

It is preferred that the first image is a CT scan or MRI with contrast (if the patient can receive contrast). After the first image, ultrasound is the recommended follow-up as there is no radiation, costs are relatively cheap and ultrasound is easy to perform. Tumor size and growth rates are evaluated with each image to determine if the tumor is changing in size or quality. Tumors are expected to change over time – the goal is to catch the dangerous ones before they grow too large or leave the kidney!!

Can these tumors be biopsied?

Percutaneous renal mass biopsy is an option for patients considering both surgery and active surveillance. Biopsy can often provide information regarding the malignant or benign nature of the mass. However, we expect most small renal masses to be low-grade, benign-behaving tumors and renal biopsy is not very good at telling the "good" cancers from the "bad." Researchers at Johns Hopkins are working right now to improve the performance of renal biopsy. Therefore, we decide on an individual basis, with each patient, if biopsy will be helpful.

What are the "triggers" for intervention?

Most renal masses grow at a slow and unpredictable rate. The average growth rate is about 1 millimeter per year, however some tumors can grow faster and some tumors can shrink away! The biggest trigger for intervention is overall tumor size. The risk of spread from the kidney increases from <1% at 2cm, to 2-3% at 3cm and 5-10% for tumors 4cm or larger.[1] Growth rate (centimeters per year) is also a consideration and tumors that grow >0.5cm/year may indicate aggressive growth. With each active surveillance image, the need for intervention is reconsidered.

Can the tumor spread while on active surveillance?

The answer to this is unfortunately, YES. However, for a well-selected patient the risk of this occurring on surveillance is very low (<2%).[2] Each patient and tumor are unique and this risk should be discussed with your urologist.

In patients who elect for delayed intervention, are the results compromised?

A study by Johns Hopkins urologists showed that a period of active surveillance did not alter results. In this study, patients delayed treatment of their small kidney mass by over 1 year. All were eventually treated with minimally invasive surgery successfully.[3]

Does Johns Hopkins have an active surveillance program for kidney tumors?

Yes. In 2009, Johns Hopkins urologists Mohamad Allaf, MD and Phillip M. Pierorazio, MD started the DISSRM (Delayed Intervention and Surveillance for Small Renal Masses) Registry. The DISSRM Registry now catalogues over 200 patients undergoing active surveillance at Johns Hopkins, Columbia University in New York, and Beth-Israel Deaconess Hospital in Boston. For more details, see our prior blog: Active Surveillance Proving Safe for Patients with Small Renal Masses.  Patients in the program are followed in an identical fashion to patients who choose not to enroll in the program (see "What does active surveillance involve?" above). The program involves regular check-ups and questionnaires regarding quality of life, anxiety, and general well-being. In addition, patients have the option of contributing blood and urine samples to look for a blood or urine marker to detect kidney cancer and answer some other important questions for this disease. Benefits to enrolling in the DISSRM Registry include help with decision-making throughout the surveillance process, the gathering of data to help the next patient with a small renal mass, ensuring follow-up with the research team at Hopkins and, lastly, is extremely easy study in which to participate. After talking with an urologist at Hopkins, a patient can sign consent forms and enroll in the study. A designated DISSRM clinic meets monthly to follow patients enrolled in the study. However, not all patients need to remain at Hopkins and some patients can follow-up remotely – so long as imaging and blood work are sent to Hopkins.


For more information regarding management of Kidney Cancer or the DISSRM Registry contact Dr. Mohamad Allaf, Dr. Phillip Pierorazio, or Tina Driscoll, the study coordinator at 410-955-0163.



[1] Thompson RH, Hill JR, Babayev Y, Cronin A, Kaag M, Kundu S, Bernstein M, Coleman J, Dalbagni G, Touijer K, Russo P. Metastatic renal cell carcinoma risk according to tumor size. J Urol. 2009 Jul;182(1):41-5. doi: 10.1016/j.juro.2009.02.128. Epub 2009 May 17.
[2] Smaldone MC, Kutikov A, Egleston BL, Canter DJ, Viterbo R, Chen DY, Jewett MA, Greenberg RE, Uzzo RG. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. Cancer. 2012 Feb 15;118(4):997-1006. doi: 10.1002/cncr.26369. Epub 2011 Jul 15.
[3] Rais-Bahrami S, Guzzo TJ, Jarrett TW, Kavoussi LR, Allaf ME. Incidentally discovered renal masses: oncological and perioperative outcomes in patients with delayed surgical intervention. BJU Int. 2009 May;103(10):1355-8

Historical Contribution: 1942, Jewett, New Method of Ureteral Reimplantation

1942
Jewett. A new method of ureteral transplantation for cancer of the bladder. Journal of Urology, 1942: (48), 489-513.

 
In the early 1940's, the mortality for extirpative bladder cancer surgery and reconstruction hovered around 50%. The mainstay for urinary diversion was the ureterosigmoidostomy, which was fraught with complications related to obstruction of the freshly implanted ureter. In the discussion, Dr. Lawrence Wharton comments that, "in spite of 65 or so techniques now available, [ureteral anastomosis] is still a dangerous operation and should never be done…" However, it was recognized that there are several circumstances, including iatrogenic ureteral injuries in addition to bladder cancer, where no other option is left and foregoing urinary diversion condemned the patient to certain death.

 
In this manuscript, Dr. Hugh J. Jewett describes 15 cases of a two-stage ureterosigmoidostomy. Without a viable option for urinary divesion, Jewett knew that patients would succumb to renal failure or be so debilitated by chronic obstruction and infection that they would be unable to survive radical cystectomy. For this operation, Jewett expanded upon a two-stage surgical technique from the 1930's – and developed a special cutting electrode to facilitate the operation. Briefly, the operation included:

Stage 1: submucosal implantation of both ureters into the sigmoid colon without a lumen-to-lumen connection. This preserved ureteral blood supply and allowed the ureter to safely anastamose to the colon. Importantly, Jewett covered the ureterocolonic anastomoses in omentum and peritoneum to preserve/enhance blood supply and healing.

 
Stage 2: Maturation of the ureterosigmoidostomies. Three or four weeks later, Jewett would take the patient back to the operating room to complete the ureterosigmoidostomy. The distal ureter was divided, giving Jewett access to the anastomosis of the ureters to the colon. Using his cutting electrode, the lumen of the bowel could be joined to the ureter, completing the anastomosis in a safe, well-vascularized fashion.

 
Outcomes
All patients had invasive urothelial cancer of the bladder. Thirteen of the fifteen patients proceeded to cystectomy after urinary diversion. Nine of the 15 were alive 1.5 years after surgery. Three died during the recovery period and three died after discharge from the hospital. All of the patients, except one, died with adequate urinary drainage and good renal function. One patient, who Jewett attributed to a technical error, died of urinary obstruction as an early electrode caused significant damage to the anastomosis. Four patients required subsequent operations due to: bowel complications, urine leak and/or abdominal infection. No patient developed an ascending pyelonephritis.

 
While recognizing that his operation carried significant morbidity and mortality, Jewett noted in his conclusions,

"In the cases which I have reported, the condition of the majority of the patients was considered hopeless, and every form of therapy had been tried elsewhere before the patient was subjected to transplantation of the ureters. In a group of patients representing better surgical risks, I believe the mortality could be considerably reduced."

 
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! 


 

Radiation Therapy after Prostate Surgery: The Guidelines Say Yes, My Doctor Says No

Some men prostate cancer are faced with the realization that treatment of their prostate cancer may require multimodal treatment including some combination of surgery, radiation therapy and/or hormone therapy. The combined ASTRO/AUA (American Society for Therapeutic Radiology and Oncology/American Urological Association) Guideline for "Adjuvant and Salvage Radiotherapy after Radical Prostatectomy" makes a number of statements regarding the use of radiation therapy after surgery that can be confusing to patients and practitioners.

In this blog we review the statements from the ASTRO/AUA Guideline regarding adjuvant radiation therapy and the data supporting them.

 

THE STUDIES

The Guidelines are supported, mostly, by the data from three randomized trials of adjuvant radiation therapy (ART) versus observation for patients after radical prostatectomy (RP). The SWOG trial began first in 1988 followed by the EORTC and most recently the ARO trial. However, the EORTC trial had more than double the sample size compared to the other two trials. All three trials enrolled patients with pathologic stage, pT3, disease and/or positive surgical margins. However, they differed in that the ARO trial excluded men with a persistently elevated PSA after RP, whereas these patients were included in the other two trials.
All three trials used a relatively low radiation dose of 60 Gray (most radiation oncologist argue that adequate, contemporary treatment of prostate cancer requires 80 Gray), and only the more recent ARO trial used modern 3-dimensional treatment planning. Central pathology review was available for the majority, but not all, patients in the 3 trials. The primary endpoint was metastasis-free survival in the SWOG study, versus progression-free survival in the other 2 trials. Finally, because it began earlier, the initial SWOG publication and a more recent update had longer follow-up than in the other trials.

 

Vital Statistics:

SWOG 8794

Thompson et al. JAMA 2006; 296: 2329.
Thompson et al. JUrol 2009; 181: 956.
Initiated: 1988
Sample Size: 425
Inclusion Criteria: pT3* and/or SM+ (Positive Surgical Margin); 15.7% pT2*
Patients with Persistent PSA Elevation following Surgery: Approximately 1/3^rd
Radiation Therapy Dose: 60-64 Gray
Primary Endpoint: Metastases-Free Survival
Median Follow-up: 12.6 years

EORTC 22911

Bolla et al. Lancet 2005; 366: 572.
Van der Kwast et al. JCO 2006; 26: 4178.
Bolla et al. Lancet. 2012 Dec 8;380(9858):2018-27
Initiated: 1992
Sample Size: 1,005
Inclusion Criteria: pT3* and/or SM+ (>1/3^rd pT2*)
Patients with Persistent PSA Elevation following Surgery: 11%
Radiation Therapy Dose: 60 Gray
Primary Endpoint: clinical or biochemical Progression-Free Survival (PFS)
Median Follow-up: 10.6 years

ARO 96-02/ AUO 09/95
Wiegel et al. JCO 2009; 27: 2898.
Initiated: 1997
Sample Size: 388
Inclusion Criteria: pT3* with or without SM+ (No Lymph Node Metastases)
Patients with Persistent PSA Elevation following Surgery: 20%, were excluded
Radiation Therapy Dose: 60 Gray (using modern 3-D conformal techniques)
Primary Endpoint: biochemical Progression-Free Survival (PFS)
Median Follow-up: 4.5 years


**DEFINITIONS 
pT2: organ-confined prostate cancer at RP
pT3: non-organ confined disease at RP (includes pT3a: extraprostatic extension and pT3b: seminal vesicle invasion)
SM+: positive surgical margins


 

THE GUIDELINE STATEMENTS

Guideline Statement 1.

• Patients who are being considered for management of localized prostate cancer with radical prostatectomy should be informed of the potential for adverse pathologic findings that portend a higher risk of cancer recurrence and that these findings may suggest a potential benefit of additional therapy after surgery. (Clinical Principle)

Guideline Statement 2.

• Patients with adverse pathologic findings including seminal vesicle invasion, positive surgical margins, and extraprostatic extension should be informed that adjuvant radiotherapy, compared to radical prostatectomy only, reduces the risk of biochemical (PSA) recurrence, local recurrence, and clinical progression of cancer.
• They should also be informed that the impact of adjuvant radiotherapy on subsequent metastases and overall survival is less clear; one of two randomized controlled trials that addressed these outcomes indicated a benefit but the other trial did not demonstrate a benefit. However, the other trial was not powered to test the benefit regarding metastases and overall survival. (Clinical Principle)
  

Guideline Statement 3.

• Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy including seminal vesicle invasion, positive surgical margins, or extraprostatic extension because of demonstrated reductions in biochemical recurrence, local recurrence, and clinical progression. (Standard; Evidence Strength: Grade A)

 

THE DATA SUPPORTING EACH STATEMENT

Biochemical Recurrence or Progression Free Survival

All three studies demonstrate a higher proportion of men experiencing a biochemical (PSA) recurrence after RP and ART. The risk of recurrence was decreased approximately 50% in meta-analysis data from all three trials including in the guideline indicating that ART reduces the risk of biochemical (PSA) recurrence in men with high-risk of recurrence after radical prostatectomy.

	Biochemical Progression-Free Survival
	Follow-up	RP+ART	RP alone	Hazard Ratio
SWOG8794	10 years	53.0%	26.0%	0.43, P<0.01
EORTC22911	10 years	60.6%	41.1%	0.49, P<0.01
ARO96-02	5 years	72%	54%	0.53, P=0.002

Locoregional and Metastatic Recurrence or Recurrence-Free Survival

This statistic refers to the proportion of patients who develop nodal metastasis or evidence of prostate cancer in the pelvis that can be treated with curative radiation. These numbers are expectedly low, even for patients with advanced disease. The ARO96-02 trial did not report locoregional recurrence, but both the SWOG and EORTC studies demonstrated a benefit for ART with regard to locoregional relapse.

	Local Relapse-Free Survival
	Follow-up	RP+ART	RP alone	Hazard Ratio
SWOG8794	10 years	8%	22%	NR, P<0.01
EORTC22911	10 years	8.4%	17.3%	0.45, p<0.01
ARO96-02	5 years	Not Reported

 
Metastatic recurrence refers to the proportion of patients who develop recurrent prostate cancer outside of the pelvis, are therefore not curable by local treatments like radiation and require systemic treatment like androgen deprivation and/or chemotherapy. The results for metastatic recurrence (and metastasis-free survival, MFS) are less clear with conflicting results among the studies. The SWOG study demonstrated a benefit to ART, while the EORTC did not and ARO96-02 has too few events at current follow-up. In the SWOG study, MFS was defined as the presence of metastases or death from any cause. In the SWOG study, 72% of the deaths occurred in men without metastases and there were only 5 more cancer deaths in the observation group – perhaps leading to the significant finding in this study.[1]

	Metastases and Metastases-Free Survival (MFS)
	Follow-up	RP+ART	RP alone	Hazard Ratio
SWOG8794	10 years	9.3%	17.5%	MFS:0.71, P=0.016
EORTC22911	10 years	10.1%	11%	MFS: 0.99, P=0.94
ARO96-02	4.5 years	2.7%	3.1%	NR

 

Overall Survival

Overall Survival (OS) was improved for patients receiving ART in the SWOG study, but not the EORTC or ARO96-02 studies. Mirroring the MFS data, there are conflicting results for OS among the studies.

	Deaths and Overall Survival (OS)
	Follow-up	RP+ART	RP alone	Hazard Ratio
SWOG8794	10 years	OS: 74%	66%	0.72, P=0.023
EORTC22911	10 years	OS: 76.9%	80.7%	1.18, P=0.2
ARO96-02	4.5 years	Deaths: 3.4%	5.0%	NR

SUBGROUP ANALYSES

All three studies consisted of a heterogeneous group of patients including patients with low-, intermediate- and high-risk features and variation in Gleason score, SM+ and pathological stage. When looking at these subgroups, ART appears to have the most benefit for patients with:

• Positive Surgical Margins (SM+)
• Gleason Sum ≥ 7

Other than biochemical (PSA) recurrence-free survival, the benefit to ART is unclear in patients with:

• Gleason 6
• Extraprostatic extension in the absence of SM+
• Seminal vesicle invasion (pT3)

A future blog will discuss the subgroup analyses in greater detail.

SUMMARY

• Adjuvant radiation therapy (ART) is an option for men with advanced prostate cancer and adverse features after radical prostatectomy.
• The ASTRO/AUA Guidelines are based on the data from three large, randomized clinical trials:
  • SWOG 8794
  • EORTC 22911
  • ARO 96-02/ AUO 09/95
• Patients who undergo ART will have an improvement in biochemical (PSA) and locoregional recurrence.
  • The impact of ART on distant metastases and overall survival is less clear.
• Subgroup analyses indicate that patients with positive surgical margins and Gleason Score ≥ 7 are most likely to benefit from ART.
  • The benefit of ART is unclear in patients with Gleason 6, extraprostatic extension or seminal vesicle invasion.

 

This blog was written by Mark W. Ball, MD. This blog is the first of a series on "Radiation Therapy after Prostate Surgery."  Dr. Ball is a 5^th year urology resident at the Brady Urological Institute at Johns Hopkins and looking forward to a career in urologic oncology.


 

 

 


[1] Cheng et al J Urol 182: 2531, 2009