UETTE CENTER. Written

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1 OUTCOME ANALYSISS 2010 DIAGNOSIS AND TREATMENTT OF URINARY TRACT CANCERS AT MARQU UETTE GENERAL CANCER CENTER Written By: Aaron P. Scholnik, MD, FACP 1

2 Diagnosis and Treatment of Urinary Tract Cancers at Marquettee General Cancer Center: Outcome Analysis 2010 andd Discussion. Cancer of the urinary tract includes, cancers arising in the excretory portion of the kidneys, the collecting system of the kidneys including the renal pelvis, ureters and the bladder. Throughout the United States, there are over 105,000 cases of urinary tract cancers diagnosed each year. When adjusted for age, this calculates to 37.2 cases per 100,000 population. The State of Michigan s rate is higher than average incidence of urinary tract cancer at per the 100,000 population per year. Nationally, the highest rates seem to be in the New England states plus New Jersey, Pennsylvania, Kentucky and Michigan. The rates of urinary tract cancer in the upper Midwest however closely approach this rate. (Figure 1) Figure 1 2

3 In addition, it should be noted that the incidencee of non invasive bladder cancer is a recurring problem. Those patients that develop this non invasive disease requiree on going treatment and surveillance and those diagnoses are not included in these statistics regardingg invasive cancers. Non invasive bladder cancers, however, are frequently the forerunners of invasive cancers that might develop later on in the same patients. The importance of urinary tract cancer is two fold: 1) it can be a major cause of cancer related death and 2) even when non fatal it can cause significant morbidityy and disability due to the biological importance of maintaining a functioning urinary tract. For instance, loss of a kidney can jeopardize health and even precipitate renal failure if the remaining kidney ceases to function properly. Removal of the bladder will createe the necessity for urostomy with its associated problems. Finally, the extensive nature of curative cancer surgery required to remove a kidney, ureter or bladder can lead to its own morbidities and mortalities. Improvements in the management techniques for urinary tract cancer are steadily decreasing the risk of morbidities and mortalities and improving the outcomes. Moreover, new medicines and new minimally invasive, anti cancer procedures are also leading to improvedd management of these cancers, decreasing side effects and improving cancer control. The lessons in basic cancer biology that we are learning from studies done on urinary tract cancers are already resulting in new treatments that specifically target abnormalities in the genetic makeup of the cancers. This willl allow us to treat the cancer more effectively while decreasing the toxicity to the patient. 3

4 In Michigan, the age adjusted rate for all invasive urinary system cancers is per 100,000 patients per year. The statistics are broken down into three anatomical areas, namely kidney and renal pelvis (even though cancers of the renal pelvis are really more similar in many ways to those of the ureter and bladder), ureter, and urinary bladder. National statistics are complete for the years 2003 thru 2007 (Figure 1) and show that out of the 525,815 cases of urinary tract cancer, 21,097 are cancer of the kidney and renal pelvis with an age adjusted incidence of cases per 100,000 per year. During the same period, Michigan had an age adjusted incidence of cases per 100,000 population per year. Cancers of the ureter are relatively uncommon. For the years 2003 thru 2007 the total incidence was 8,234 and over the same time period in Michigan the total number was 323. Again the age adjusted incidence in Michigan is 0.63 cases per 100,000 population per year which is slightly higher than the national average of 0.59 cases per 100,000 population per year. In the five years 2005 through 2009 the MGCC diagnosed and treated 123 patients with malignancies of the kidney and renal pelvis, 4 patients with cancer of the ureter and 157 patients with cancer of the bladder. This is approximately the same proportion as these cancers are diagnosed throughout the United States. Two thirds of urinary tract cancers occur in the bladder. Of the 525,815 urinary tract cancers, 303,028 arose in the bladder. The U.S. age adjusted incidence rate is cases per 100,000 population per year. During this same period, Michigan had 12,415 cases for an age adjusted incidence rate significantly higher than the national average at cases per 100,000 per year, ranking 11 th highest in the 50 United States in incidence of bladder cancer. The most common type of cancer occurring in the kidney is renal cell carcinoma. These cancers arise within the outer portion of the kidney called the cortex and account for 85% of primary kidney cancers. Incidence in males exceeded that in females for kidney and renal pelvis cancer by a ratio of 3:2. During the five year period of 2005 through 2009, MGCC cared for 72 men and 53 women with kidney and renal pelvis cancer. As in the rest of national statistics, the onset for these cancers were slightly earlier in men than in women however no cases were diagnosed in patients less than 40 years of age. The vast majority of patients were diagnosed in age range of 60 to 90 years of age (Graph 1). 4

5 Males Diagnosed with Kidney & Renal Pelvis Cancer from at MGH (72) Age (3) Age (8) Age (10) Age Age (13) Age (23) Females Diagnosed with Kidney & Renal Pelvis Cancer from at MGH (53) Age (4) Age (5) Age (8) Age (7) Age (13) Age (16) Years Years Years Years Years Years Years Years Years Years Years Years Years Graph 1 Although there are several types of renal cell carcinoma, it is not clear that variations from the more common clear cell carcinoma have a significantly different natural history or response to treatment. The most common symptom of kidney cancer has been and continues to be blood in the urine (Hematuria) (Table 1). Four decades ago the classic triad of flank pain, hematuria and a palpable abdominal renal mass was thought to be the hallmark of renal cell carcinoma. Now (2009), only about 9% of patients actually present with this classic triad which represents advanced disease (Table 1) ). Hematuria still occurs in 40% of patients as the presenting symptom as well as flank pain. Because of the location of the kidney, a palpable mass is usually noted only on thin individuals or in renal cell carcinomaa arising in the lower pole of the kidney. Occasionally the cancerr may obstruct the venous drainage of the abdomen and pelvis causing dilated veins andd swelling in the pelvis. Kidney cancers can also cause distant abnormalities called paraneoplastic syndromes which do not necessarily indicate spread of the cancer but rather the secretion of inflammatoryy substances by the cancer into the blood stream. These include anemia, liver enzyme elevations, fever, weight loss, fatigue and elevated calcium. Renal cell carcinomas can also spread or metastasize to otherr areas of the body including lymph nodes, liver, bone and lung. 5

6 KIDNEY, BLADDER, RENAL PELVIS & URETER CASES PRESENTING SIGNS & SYMPTOMS TOTAL CASES SYMPTOMS PERCENT OF TOTAL CASES HEMATURIA 24(50%) WEIGHT LOSS OVER 10# 2(4%) CHANGE IN BOWEL HABITS 2(4%) URINARY FREQUENCY 3(6%) FREQUENT MICUTURITION 1(2%) DYSURIA 1(2%) CHANGE IN STREAM 3(6%) DYSPNEA 1(2%) UNEXPLAINED FEVER 1(2%) PALPABLE LUMP OR THICKENING 2(4%) OTHER 12(25%) NO SYMPTOMS/ASYMPTOMATIC 2(4%) UNKNOWN 4(8%) Table 1 Evaluation of kidney cancer generally includes radiologic studies such as CT that include the chest and abdomen. Intravenous contrast is used when possible to evaluate whether there is involvement of the renal vein or inferior vena cava as well as to highlight any areas of metastases. Radionuclide studies such as bone scans and PET scans are not indicated in the initial work up, evaluation and staging of renal cell carcinomas. These studies are reserved for special situations because renal cell carcinomas are rather inconsistent in their ability to be detected by PET scans and bone scans. For those kidney cancers which are localized to the kidney, surgical removal can be curative. For patients who are medically unable to withstand a radical nephrectomy or who have poor renal function 6

7 that requires preservation of as much of the affected kidney as possible, partial nephrectomy or radiofrequency ablation (RFA) can be used. Even in cases where the cancer has metastasized but is causing paraneoplastic syndromes (as mentioned above) or causing other serious symptoms, nephrectomy can be useful to decrease these symptoms and improve the patient s quality of life. Moreover, removal of the bulk of tumor that is located in the kidney may increase the effectiveness of some of our newer treatments. Not all lesions that appear to be tumors in the kidney are necessarily cancers. Cancer must be distinguished predominately from cysts and benign tumors. Moreover, small cancers in older patients may remain stable for many years and can sometimes be observed. Occasionally, radiologic studies other than CT scanning have been invaluable to distinguish benign from malignant lesions of the kidney. These studies include ultrasound and MRI. There are several inherited conditions in which the risk of renal cell cancer is significantly increased. These include Von Hippel Lindau syndrome and Tuberous Sclerosis. There may also be an increased risk of kidney cancer in patients who had prior kidney radiation exposure and in younger patients who have end stage renal disease on chronic dialysis. A strong family history of renal cell cancer should also prompt periodic screening for renal cell cancer. A specific familial type of renal cell cancer called Hereditary Papillary Renal Cell Carcinoma tends to cause multiple cancers over time suggesting that nephron sparing surgery rather than nephrectomy would be the appropriate management for these unusual situations. One of the most common oncogenetic abnormalities seen in renal cell cancers is the auto activation of the Hypoxia Induced Factor (HIF) system. HIF results in over secretion of vascular endothelial growth factors (VEGF) and other substances that stimulate growth of the blood vessels that help support tumor growth. In addition, there is over activation of other genetic factors (oncogenes) in the m TOR and MAP Kinase pathways which control or stimulate cell division. Also there is frequently loss of tumor suppressors which, in their normal function, would cause programmed cell death or apoptosis in the cells with the above mentioned genetic abnormalities. Most of the medicines that have been recently developed to effectively treat advanced renal cell cancer work on one or several of these mechanisms. Renal cell cancers are graded according to the differentiation of the cells. The most common classification is the Fuhrman Grading System, Figure 2. Table 2. 7

8 S Simplified Fuhrman Grading Grade 1 Grade 2 Grade 3 Grade 4 Small, round, dark lymphocyte-like nuclei with without visible nucleoli Inconspicuous nucleoli, visible only at X (nuclei usually small and uniform with open, finely granular chromatin) Prominent nucleoli, easily visible at 100X (nuclei usually mildly to moderately pleomorphic) Markedly pleomorphic, bizarre nuclei, giant cells, multiple nucleoli Surgical Pathology Criteria Standford School of Medicine, Standford University Medical Center; ; updated 1/24/2011 Figure 2 8

9 KIDNEY, RENAL PEVIS, URETER & BLADDER CASES DIAGNOSED AT MARQUETTE GENERAL HOSPITAL BY GRADE/DIFFERENTIATION 2005, 2006, 2007, 2008 & 2009 GRADE/DIFFERENTIATION TOTAL # OF CASES (PERCENT OF TOTAL) SITE GRADE I GRADE II GRADE III GRADE IV UNKNOWN KIDNEY & RENAL PELVIS 9(7%) 48(39%) 38(31%) 5(4%) 24(19%) 124() URETER 0(0%) 1(25%) 2(50%) 1(25%) 0(0%) 4() BLADDER 66(42%) 11(7%) 52(32%) 18(12%) 10(6%) 157() Table 2 9

10 The anatomical stagingg system classifies renal cell cancers byy the size and location of the tumor, involvement of lymph nodes and distant metastasis (TNM classification refer to Appendix). Various systems of combinations of grade, stage and patient symptoms and functional status have been devised to help predict how well patients will do and to help decide what type of treatment would be most successful. Because of the highly vascular nature of many renal cell carcinomas, surgery may be more successful by blocking off the blood supply to the kidney just before surgery. This is often done using interventional radiology techniques; using catheters threaded up through the arterial system into the arteries of the kidney to administer treatment that will specifically block thee arteries necessary to improve surgical outcome and decreasee bleeding. One of the new agents available for treatment of recurrent or metastatic renal cell carcinoma is Bevacizumab (Avastin) which helps to destroy circulating vascular endothelial growth factor (VEGF). Oral medications called Tyrosine Kinase Inhibitors such as Sorafinib (Nexavar) and Sunitinib (Sutent) act on the newly growing blood vessel cells in the tumor as opposed to acting on the VEGF itself. Other agents including I. V. Temsiroimus and oral Everolimus have been developed to work on the m TOR system to inhibit cancer cell division. This is a major area of cancer drug research and many new drugs are in the process of being discovered and evaluated. Marquette General Cancer Center (MGCC) has treated patients with renall cell carcinoma with various sequences and combinations of the treatments mentioned above depending on the status of the cancer and health of the patient (Table 3). Most patients had some type of surgical procedure, usually nephrectomy, or in the case of cancers of the renal pelvis, nephroureterectomy. Some patients with more advanced disease have received treatment with all fourr classes of drugs that I mentioned. The MGCC participated in the extended access trials of Sorafinib (Nexavar) making this new drug available to patients with recurrent or metastatic renal cell carcinoma even before it was available commercially. 10

11 KIDNEY & RENAL PELVIS CANCER DIAGNOSED AT MARQUETTE GENERAL CANCER CENTER BY TREATMENT TREATMENT TOTAL: Radical Nehprectomy Radical Nephrectomy Chemotherapy Radical Nephrectomy Radiation Nephrectomy, Ureterectomy, Partial Cystectomy Nephroureterectomy Nephroureterectomy w/chemotherapy Chemoembolization Radiofrequency Ablation Systemic Chemotherapy Only Biopsy Only Radiation Only Total: Table 3 Carcinoma of the renal pelvis, ureter and bladder can, in many ways, be considered as manifestations of the same disease. Under the microscope, these cancers appear very similar and are, as a class, called urothelial or transitional cell carcinomas. The same lining cell surface or urothelium covers the inside of the renal pelvis, the ureter and the urinary bladder. It is felt that most urothelial carcinomas are caused by interaction of some genetic pre disposition to cancer with environmental exposure to toxins (Table 4). Because one of the functions of the kidney is to excrete toxins out of the body, the urothelial lined system of the renal pelvis, ureter and bladder are exposed to higher levels of these toxins. While the urine flows through the renal pelvis and ureter into the bladder and therefore has relatively brief contact with the urothelium in the upper tracts of the urinary collecting system, the urine sits for hours in the urinary bladder until voiding. Thus the urothelial lining of the bladder has a much longer, and more concentrated exposure to urinary toxins than the ureter and renal pelvis. Moreover, the surface area of the urinary bladder is larger than that of the ureters and the renal pelvis thus creating a greater surface area and greater chance for cancer to occur. 11

12 Many of the chemicals associated with urothelial cancers have not been completely identified. Most of these compounds fall into the category of aromatic amines as well as alanine dyes and other aromatic compounds including some solvents such as benzene. One common non occupational source of these toxins can be exposure to both primary and secondary cigarette smoke (Table 4). CONTRIBUTING RISK FACTORS IN PATIENTS DIAGNOSED WITH KIDNEY, RENAL PELVIS, BLADDER OR URETER CANCER AT MARQUETTE GENERAL HOSPITAL 2005, 2006, 2007, 2008 & TOTAL CASES NUMBER (PERCENT OF RISK FACTOR TOTAL CASES) YES 70(25%) PATIENT HISTORY OF OTHER CANCER FAMILY HISTORY OF KIDNEY, RENAL PELVIS, BLADDER OR URETER CANCER OCCUPATIONAL RISKS ALCOHOL USE SMOKING HISTORY NO 211(74%) UNKNOWN 4(1%) YES 10(4%) NO 161(56%) UNKNOWN 114(40%) YES 12(4%) NO 68(24%) UNKNOWN 205(72%) YES 97(34%) NO 120(42%) UNKNOWN 68(24%) NONE, NEVER SMOKED 62(22%) STOPPED SMOKING MORE THAT 5 98(34%) YEARS PREVIOUSLY LESS THAN 25 PACK YEARS 10(4%) PACK YEARS 24(8%) PACK YEARS 10(4%) 100 OR MORE PACK YEARS 3(1%) CIGAR OR PIPE USUAGE 8(3%) SNUFF/CHEWING TOBACCO 1(LESS THAT 1%) SMOKER, UNKNOWN # OF PACK 35(12%) YEARS SECONDHAND SMOKE EXPOSURE 0(0%) UNKNOWN/NOT STATED 34(12%) Table 4 The latent period (the period between exposure to a cancer inducing toxin and the first appearance of the cancer) is fairly long. Most urothelial cancers do not occur until the fifth, sixth and seventh decades 12

13 of life. They are more common in men than in women and this may have some relationship to toxin exposure over a lifetime. (Table 5) KIDNEY, BLADDER, RENAL PELVIS & URETER CASES DIAGNOSED AT MARQUETTE GENERAL HOSPITAL 2005, 2006, 2007, 2008 & 2009 BY SEX VS 2009 CASES MALES(M) VS FEMALES(F) AGE AT DIAGNOSIS 0 19 YEARS COMBINED YEARS 2005, 2006, 2007& 2008, 2009 M F M F M F M F M F M F % 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% YEARS 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% YEARS YEARS YEARS YEARS YEARS YEARS YEARS TOTAL NUMBER OF CASES % 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% % 9% 8% 0% 8% 0% 7% 11% 0% 0% 8% 6% % 5% 5% 6% 19% 22% 14% 11% 14% 0% 16% 11% % 33% 24% 50% 6% 11% 28% 30% 39% 41% 33% 37% % 29% 40% 31% 28% 28% 30% 22% 22% 25% 32% 27% % 24% 18% 13% 33% 28% 14% 19% 19% 17% 23% 23% % 0% 5% 0% 6% 11% 7% 7% 6% 17% 7% 7% Table 5 In cases of urothelial cancer of the renal pelvis, the most frequent treatment and the treatment with greatest curative potential for localized disease is nephrectomy along with the removal of the ureter. 13

14 For more advanced cases which are not operable, radiation therapy and chemotherapy with agents such as carboplatin and gemcitabine may be useful. For those raree cancers occurring within the ureters itself, surgery or radiation therapy may sometimes be curative especially if the cancer in the ureter is small and occurs in only a short segment. Cancers of the bladder have the advantage of being readily and frequently observable through cystoscopy. The ureter and renal pelvis can also be observedd using ureteroscopy, but this is somewhat more complex. Bladder cancers, as with cancers of the ureters, renal pelvis and kidney are being more frequently recognized because of diagnostic innovations and are thereforee being diagnosed at an earlier stage (Table 6). While the incidence may be increasing, the stage of the disease at the time of diagnosis is decreasing and the death rate from these cancers will eventually decrease if this trend continues. STAGE AT DIAGNOSIS - UROTHELIAL CANCERS MGH CC NCDB Kidney and Renal Pelvis Cancers Stage 0 Stage 1 Stage II Stage II II Stage IV Dx Dx Total MGH CC NCDB Bladder Cancers Stage 0 Stage 1 Stage II Dx Dx Stage II II Stage IV Total MGH CC NCDB Ureter Cancers Stage 0 Stage 1 Stage II Dx Dx Stage II II Stage IV Total Table 6 14

15 It is estimated that in 2010 there were approximately 70,5000 new cases of bladder cancer diagnosed in the United States and approximately 14,700 deaths due to bladder cancer. Urothelial cancers of the bladder occur much more frequently in men than in women by over a 2.5 to 1 ratio (Graph 2). A higher proportion of early onset bladder cancers in the age 50 to 59 ranges weree seen in men which is consistent with national statistics. The overwhelming majority of patientss with bladder cancer presented between age 60 and age 90. Females Diagnosed with Bladder Cancer from at MGH Age (3) Age (2) Males Diagnosed with Bladder Cancer from at MGH Age (11) Age (10) Age (12) Age (13) Agee (25) Age (27) Age (12) Age (42) Years Years Years Years Years Years Years Years Years Years Graph 2 Some bladder cancers are diagnosed even before they begin to invade the wall of the bladder (also called in situ lesions). These, as well as minimally invasive T11 lesions, have very little risk of spreading and causing death but will frequently recur sometime over a patient s lifetime and may eventually become more invasive, more undifferentiated, and may thenn metastasize. In addition to radiologic studies and direct visualization of thee urothelium through cystoscopy and ureteroscopy, early detection of urothelial cancers can also be assisted by analyzing urothelial cells shed into the urine and voided. Urothelial cancers tend to have certain recurring chromosomal abnormalities and various genetic tests have been developed to help identify malignant cells in the urine. Perhaps the most widely used screening test with urotheilial cells in the urine is the UroVysion test which tests for improper number of chromosomes 3, 7 and 17 or the loss of a specific part of the 9 th chromosome. 15

16 The primary means of control of any early bladder cancer is to resect it through the cystoscope and then to observe for recurrence carefully (Table 7). Recurrence re resection and then installation of various medicines into the bladder to kill off potential cancer causing cells will decrease or delay subsequent recurrences. BLADDER CANCER DIAGNOSED AT MARQUETTE GENERAL CANCER CENTER BY TREATMENT TREATMENT TOTAL: Transurethral Resection Bladder Tumor (TURBT) TURBT Intravesical TURBT Chemotherapy TURBT Radiation and Chemotherapy TURBT Radiation Cystectomy Cystectomy Chemotherapy Cystectomy Radiation Cystoprostatectomy Radiacal Cystoprostatectomy Chemotherapy Chemotherapy Only Radiation & Chemotherapy no surgery Biopsy Only Biopsy Only w/chemotherapy or Radiation Surgery w/chemotherapy Laser Ablation No Treatment Total: Table 7 16

17 The most frequently used topical medicine instilled into the bladder (intravesicle treatment) is a weakened strain of the tuberculosis bacterium called BCG which induces, with repeated installations into the bladder, a potent, immunologically mediated, reaction of the lining of the bladder which may kill those urothelial cells which have developed pre cancerous abnormalities but which have not yet become cancerous. Various chemotherapy agents have also been instilled into the bladder for those cases where BCG has been ineffective, however chemotherapy forms of intravesicle therapy appear to be less effective than BCG. After more than one recurrence of superficial bladder cancer, the risk of presenting with more advanced disease is high enough that sometimes removal of the bladder (cystectomy) is recommended prophylactically. Urothelial cancer is felt to be a field effect, meaning that anything that affects one part of the urothelial system may very well affect other areas. Therefore it is not uncommon for people who have developed cancers of the renal pelvis or upper urinary tract to later develop the same cancer in the lower ureter or bladder. This is why it is common to remove all the ureter along with the kidney and renal pelvis when a cancer of the renal pelvis is discovered. These patients continue to be at higher risk for the potential development of cancer of the bladder as well. Patients who have already had one cancer of the bladder are at high risk of recurrences because of the abnormalities that have been induced in the entire urothelium ( field effect ). For urothelial cancers that are so locally extensive that they cannot be completely removed or which have already spread to distant organs, chemotherapy and radiation therapy have been used. The most important chemotherapy agents appear to be platinum containing chemotherapy drugs, especially cisplatin and carboplatin, in conjuction of either paclitaxel (Taxol) or gemcitabine (Gemzar). For metastatic or advanced muscle invasive urothelial cancer of the bladder the MVAC (methotrexate, vinblastine, Adriamycin (doxorubicin), and Cisplatin) regime has also been used. This may be marginally more effective than combinations of Platinum plus Gemzar but has more toxicity and thus is often appropriate only for those with excellent kidney function and no other significant illnesses. Advanced age may also predispose to increased toxicity from the MVAC regime and preclude its use. Since most bladder cancers occur in older patients, the combination of platinum containing chemotherapy agents along with gemcitabine has become the most frequently used systemic treatment (refer to Table 7). 17

18 As with renal cell carcinomas, the over secretion of VEGF in urothelial cancers appears to be a major mechanism by which cancers are able to attract blood vessels and thus receive sufficient oxygen and nutrition to grow and spread. MGCC is participating in a national trial comparing the standard therapy of Carboplatin and Gemcitabine to the same combination plus the drug Bevacizumab ( Avastin) a monoclonal antibody against VEGF. The rather rare ureter cancer occurs at a later age with two cases occurring in the 60 s and two in the 80 s (Graph 3). Three cases occurred in men and one in a woman (Graph 3). Females Diagnosed with Ureter Cancer in at MGH (1) Males Diagnosed with Ureter Cancer from 2005 to 2009 at MGH Age (1) Age (1) Age (2) Years Years Years Graph 3 Two of the four ureterr cancers weree treated with Nephrectomy and Chemotherapy, one with Nephroureterectomy and one with Ureteral Resection (Tablee 8). URETER CANCER DIAGNOSED AT MARQUETTE GENERAL CANCER CENTER BY TREATMENTT TREATMENT Nephrectomy w/chemotherapy Nephroureterectomy Ureteral Resection Total: TOTAL: Table 8 18

19 One of the inovations in the management of muscle invasive bladder cancer, which has been debated for years and which has become more acceptable after several randomized clinical trials, is the treatmentt with combined chemotherapy and radiation therapy using cystectomy only for salvage if there is local recurrence. In some studies, survival appears to be equivalent. The toxicity of the chemotherapy and radiation therapy may be somewhat greater than thatt of radical cystectomy. However, in those patients who are capable of withstanding the cystectomy; most of them are able to also tolerate combined chemotherapy and radiation therapy.. The benefit of chemotherapy and radiation is that bladder function may be preserved. This will hopefully stimulate a study to delineate which sub groups of patients may benefit more from one treatment than another. Our urological surgeons over the years performed 92 nephrectomies (Refer to Table 3) ). Some of the nephrectomies were combined with radiation orr chemotherapy depending on the cell type (renal celll carcinoma versus urothelial cancer) (Refer to Tablee 7). Likewise, all malignant biopsies of the bladder and cystectomies were combined with intervesical chemotherapy, radiation therapy and systemic therapy as appropriate for the stage and grade of the bladder cancers treated (Refer to Table 7). The 2009 cases of urinary system cancer treated at the Marquette General Cancer Center are analyzed by site and histology in Table 9 &

20 KIDNEY, RENAL PELVIS, BLADDER & URETER CASES DIAGNOSED AT MARQUETTE GENERAL HOSPITAL BY HISTOLOGY CASES TOTAL HISTOLOGY KIDNEY & RENAL PELVIS (20 CASES) URETER (2 CASES) BLADDER (27 CASES) PAPILLARY TRANSITIONAL(UROTHELIAL) CELL CARCINOMA (INVASIVE) 3(15%) 2() 10(37%) TRANSITIONAL(UROTHELIAL) CELL CARCINOMA (INSITU) 0(0%) 0(0%) 11(41%) SIGNET RING CELL CARCINOMA 0(0%) 0(0%) 1(4%) LYMPHOEPITHELIAL CARCINOMA 0(0%) 0(0%) 1(4%) CLEAR CELL CARCINOMA 7(35%) 0(0%) 0(0%) RENAL CELL CARCINOMA 7(35%) 0(0%) 0(0%) PAPILLARY ADENOCARCINOMA 2(10%) 0(0%) 0(0%) RENAL CELL SARCOMATOID 1(5%) 0(0%) 0(0%) Table 9 20

21 KIDNEY, RENAL PELVIS, BLADDER & URETER CASES DIAGNOSED AT MARQUETTE GENERAL HOSPITAL BY GRADE/ DIFFERENTIATION CASES TOTAL KIDNEY & RENAL PELVIS URETERR BLADDER GRADE/DIFFERENTIATION (20 CASES) (2 CASES) (27 CASES) GRADE I 0(0%) 0(0%) 9(33%) GRADE II 8(40%) 0(0%) 4(15%) GRADE III 7(35%) 2() ) 6(22%) GRADE IV 1(5%) 0(0%) 6(22%) UNKNOWN GRADE/DIFFERENTIATION 4(20%) 0(0%) 2(8%) Table 10 21

22 Graph 4, Kidney and Renal Pelvis Recurrence by Stage Diagnosis at MGH Cancer Center shows the pattern of recurrence for cancers of the kidney and renal pelvis. Of 108 total cases, 52 presented with localized disease and 56 cases had already spread at the time of diagnosis. With a follow up of up to 5 years, 59% are free of disease. Of the 566 patients presenting with regional spread, almost half were never able to become disease free, while all of the patients presenting with localized disease were initially rendered free of cancer. KIDNEY and RENAL PELVIS Recurrence by Stage Diagnosis at MGH Cancer Center NUMBER OF KIDNEY AND RENAL PELVIS CASES WHICH RECURRED NO RECURRENCE (64) DISTANT (5) TOTAL CASES UNKNOWN STAGE of NEVER DISEASE RECURRENCE FREE (29)) (10) STAGE AT DIAGNOSIS LOCAL (52) REGIONAL (56) EXTENT OF RECURRENCE NO RECURRENCE (64) REGIONAL (56) 20 LOCAL (52) 444 DISTANT (5) 3 2 UNKNOWN STAGE of RECURRENCE (10) 4 6 NEVER DISEASE FREE (29) 29 0 Graph 4 22

23 Graph 5, Bladder Recurrence by Stage at Diagnosis at MGH Cancer Center shows the recurrence pattern of Marquette General Cancer Center bladder cancer patients. 130 of the 151 cases presented with diseasee confine to the bladder. 51 of these patients have had no recurrence. None of the in situ cancers had a distant recurrence but about 40% off in site cancers recurred with locally invasive disease. This indicates the importance of regular andd thorough urologic follow up for all in site or minimally invasive bladder cancers. NUMBER OF BLADDER CASES WHICH RECURRED BLADDER Recurrence by Stage at Diagnosis at MGH Cancer Center TOTAL CASES 151 STAGE AT DIAGNOSISS INSITU (75) LOCAL (55) REGIONAL (16) DISTANT (5) STAGE OF RECURRENCE NO RECURRENC E (54) INSITU (75) 34 LOCAL (55) 17 REGIONAL (16) 3 DISTANT (5) 0 UNKNOWN NEVER REGIONAL STAGE OF INSITU (9) LOCAL (36) DISTANT (8) DISEASE (3) RECURRENC FREE (22) E (19) Graph 5 23

24 Graph 6, Ureter Recurrence by Stage at Diagnosis at MGH Cancer Center shows the pattern of recurrence with cancer of the ureter. With the scarcity of this cancer, statistics are not meaningful. All 4 of our cases presented with regional involvement and one with distant disease as well. All 3 casess with regional invasion (retroperitoneal) only remain disease free. URETER Recurrencee by Stage at Diagnosis at MGH Cancer Center NUMBER OF URETER CASES WHICH RECURRED TOTAL CASES 4 NO RECURRENCE (3) NEVER DISEASE FREE (1)) STAGE OF RECURRENCE STAGE AT DIAGNOSIS REGIONAL (4) REGIONAL (4) NO RECURRENCE (3) 3 NEVER DISEASE FREE (1) 1 Graph 6 24

25 Survival data for urinary tract cancers are presented for the years to ensure that records for a minimum of 5 years are available (Graphs 7, 8 9). Several caveats are needed to interpret this data and to compare MGH data with the National Oncology Data Base (NODB).. The death rates are not cancer specific, that is, recorded deaths in cancer patients may often be due to other health problems that also occur in the older age range of most urinary tract cancer patients. Also, the numbers of the subcategories of urinary tract cancers are too small for statistically significant survival comparisons to be drawn versus the NODB data. The bar graphs and tables in Graphs 7, 8, & 9 show the comparative 1 5 year survival data by stage for MGH side by side with NODB. With the caveats as above, the survival data appear quite similar for kidney and renal pelvis (Graph 7), ureter (Graph 8) and bladder (Graph 9).. As new diagnostic and therapeutic techniques are developedd and incorporated into practice, it is anticipated that the quality as well as the quantity of survivorship will improve. To this goal the MGCC has dedicated itself. 25

26 5 YEAR SURVIVAL FOR KIDNEY & RENAL PELVIS CASES DIAGNOSED AT MARQUETTE GENERAL VS NODB 1998,1999,2000,2001,2002 BY STAGE AT DIAGNOSIS 90% 80% 70% 60% 50% 40% 30% 95% 84% 73% 86% 68% 64% 96% 89% 81% 71% 57% 94% 84% 74% 86% 57% 85% 66% 55% 52% 20% 43% 36% 10% 0% STAGE O MGH 90% 79% STAGE O NODB 79% 64% 92% 85% STAGE I STAGE I MGH NODB 57% STAGE II MGH 89% 79% STAGE II NODB 79% 57% STAGE III MGH 74% 60% STAGE III NODB 26% 13% 9% 9% STAGE IV MGH DX 1 YEAR 2 YEAR 3 YEAR 4 YEAR 5 YEAR 20% 14% 10% 8% STAGE IV NODB Stage 0 Stage 0 Stage 1 Stage 1 Stage 2 Stage 2 Stage 3 Stage 3 Stage IV Stage IV MGH NCDB MGH NCDB MGH NCDB MGH NCDB MGH NCDB Dx YEAR YEAR YEAR YEAR YEAR Graph 7 26

27 5 YEAR SURVIVAL FOR BLADDER CASES DIAGNOSED AT MARQUETTE GENERAL VS NODB 1998,1999,2000,2001,2002 BY STAGE AT DIAGNOSIS 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 94% 85% 75% 64% 60% STAGE O MGH 96% 92% 87% 83% 78% 91% 77% 63% 54% 46% STAGE STAGE I O NODB MGH 92% 85% 78% 72% 67% STAGE I NODB 76% 62% 52% 43% 38% 73% 59% 50% 44% 40% 62% 62% 50% 38% 38% STAGE IISTAGE II STAGE MGH NODB III MGH 66% 48% 39% 34% 30% STAGE III NODB 45% 27% 9% 9% 9% STAGE IV MGH DX 1 YEAR 2 YEAR 3 YEAR 4 YEAR 5 YEAR 43% 23% 17% 14% 12% STAGE IV NODB Stage 0 Stage 0 Stage 1 Stage 1 Stage 2 Stage 2 Stage 3 Stage 3 Stage IV Stage IV MGH NCDB MGH NCDB MGH NCDB MGH NCDB MGH NCDB Dx YEAR YEAR YEAR YEAR YEAR Graph 8 27

28 5 YEAR SURVIVAL FOR URETER CASES DIAGNOSED AT MARQUETTE GENERAL VS NODB 1998,1999,2000,2001,2002 BY STAGE AT DIAGNOSIS 90% 80% 70% 60% 50% 40% 92% 82% 74% 91% 76% 87% 76% 30% 65% 62% 20% 50% 50% 50% 41% 46% 10% 0% 50% 88% 77% 82% 71% STAGE STAGE STAGE STAGE O MGH O NCDB I MGH I NCDB STAGE II MGH 73% 55% 0% 0% 53% 35% 28% 0% 0% 0% 0% 0% 0% 31% 21% 18% 14% STAGE STAGE II NCDB III MGH STAGE III NCDB STAGE STAGE IV MGH IV NCDB DX 1 YEAR 2 YEAR 3 YEAR 4 YEAR 5 YEAR Stage 0 Stage 0 Stage 1 Stage 1 Stage 2 Stage 2 Stage 3 Stage 3 Stage IV Stage IV MGH NCDB MGH NCDB MGH NCDB MGH NCDB MGH NCDB Dx YEAR YEAR YEAR YEAR YEAR Graph 9 28

29 APPENDIX 29

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