BE A PARTNER . . . NOT A PATIENT
The primary mission of the Texas Cancer Center is to show you the great body of medical evidence which supports conservative (limited) surgery for patients with cancer. Patients and doctors alike have a natural desire to eliminate every last cancer cell - "Get It ALL." Medical research tells us that the entire tumor should be removed. But, the surgeon does not need to perform radical surgery to eradicate nearby microscopic cells which might be cancerous.
This treatment strategy has been proven to be successful for breast cancer, melanoma, the soft tissue sarcomas, and other cancers. All available medical evidence suggests that this conservative treatment strategy is successful for patients with bladder cancer as well.
Removal of the bladder is the most common treatment. Even bladder-sparing surgery often involves the aggressive use of radiation and chemotherapy. But limited surgery alone, which saves the bladder, cures just as many patents as more aggressive treatment. The Texas Cancer Center encourages limited surgery, as practiced by Dr. H.W. Herr at Memorial Sloan-Kettering Hospital in New York. Additional medical research supporting our recommendations can be found in our "Medical Research" section. Most of this research is directly linked to the National Library of Medicine. There are no medical studies which refute this conservative treatment strategy.
INTRODUCTION
Bladder cancers represent about 5% of all cancers in the United States. It is estimated that about 52,000 new cases appear each year and that about 10,000 patients die of this disease. Men have been three times as likely to get bladder cancer, because of their exposure of carcinogens at work. Over 70% of patients with bladder cancer now live five years or longer due to the early detection of this disease.
(Return to Top)
STAGES OF DISEASE
There are currently two staging systems is use. Shortly after World War II urologists accepted the Jewett-Strong-Marshall system, which stages bladder cancer from stage 0 to stage D. More recently The International Union Against Cancer (UICC) and the American Joint Committee on Cancer Staging developed a system based upon the TNM method. It is based upon three criteria: (1) the size of the tumor [T], (2) the involvement of regional lymph nodes [N], and (3) the presence or absence of distant metastases [M]. The TNM system is widely used for all solid tumors, but in its complete form, it is difficult to use.
The TNM Method
Tumor Size (T)
Ta benign papillomas
Tis carcinoma in situ.
T1 Tumor does not penetrate the lamina propria.
T2 Tumor invades the superficial muscle.
T3a Tumor invades the deep muscle.
T3b Tumor invades the fat around the bladder.
T4 Tumor invades a nearby organ.
Nodal Metastases (N)
N0 No cancer in the lymph nodes.
N13 Lymph nodes involved with cancer.
Distant Metastases (M)
M0 No distant metastases
M1 Distant metastases are present.
The Jewett-Strong-Marshall System
Stage 0 - A superficial cancer that is not invasive. This includes benign papillomas (Ta) and carcinoma in situ (Tis). These lesions have almost no potential to spread. This fiveyear survival rate is over 90%.
Stage A - The cancer invades into the submucosa, the layer beneath the transitional cells, but not through the lamina propria. (T1, N0, M0). The fiveyear survival rate is over 75%.
Stage B1 - The cancer penetrates through the lamina propria and begins to invade the bladder muscle (T2, N0, M0). The fiveyear survival rate is about 60%.
Stage B2 - The tumor invades deeply into the muscle (T3a, N0, M0). The fiveyear survival rate is about 40%.
Stage C - The tumor invades into the fat around the bladder (T3b, N0, M0). The fiveyear survival rate is about 30%.
Stage D1 - The tumor involves adjacent organs, (e.g., the upper urethra, the lining of the bladder or rectum, pelvic bones) or pelvic lymph nodes. (T4 or N13) The fiveyear survival rate is about 5%.
Stage D2 - Distant metastases are present. (M1) The fiveyear survival rate is about 5%.
(Return to Top)
TYPES OF TREATMENT
Surgery
Radical Cystectomy - Invasive bladder cancer has been treated with removal of the entire bladder, the surrounding tissue and fat, and the pelvic lymph nodes. Additional surgery depends upon the sex of the patient. In women, the uterus, fallopian tubes, ovaries, urethra and anterior portion of the vaginal are removed. In men, the prostate gland and seminal vesicles are removed.
The urinary tract can be reconstructed using a piece of intestine an ileal conduit. A segment of small intestine is removed from the intestinal tract. One end is sewn off and the other opens to the outside of the body through the abdominal wall. The ureter carries urine from the kidney to intestinal segment, which serves as a bladder. It is called an ileostomy. Patients urinate into a plastic bag attached to their side. Sometimes a pouch can be constructed inside the patient from a segment of intestine. In men this pouch may be sewn to the urethra allowing nearly normal urination. In women the urethra is usually removed with the bladder and the internal pouch must be catheterized about three times a day.
Men used to become impotent, because the nerves to the penis were cut. But since the late 1980's some urologists have been using a technique which spares these nerves, and preserves erectile function in most men. In cases where impotence occurs, it can be improved with penile implants.
Partial cystectomy - A full thickness excision of the cancer is removed with a 2 cm margin. Tests should be done to determine that the remaining bladder wall is free of tumor. The recurrence rates following this procedure are very high 70% in some studies. Chemotherapy is often included as part of this therapy. Some urologists recommend low dose radiation (1000 1200 cGy) prior to surgery to reduce tumor cell implantation during the surgery. The pelvic lymph nodes are often removed.
Most urologists have strict criteria for partial cystectomy. Patients should have a solitary tumor limited to the bladder, which can be excised with an adequate margin. There should be no prior history of bladder cancer or other cancer present, either tumors or atypical cells. The tumor should not invade the lower part of the bladder (trigone) or the prostate gland. These strict criteria are now being relaxed.
Transurethral resection (TUR) or fulguration - This involves the cutting or burning of tumors through a scope. Tumors must be accessible to the resecting scope. Most urologists would require the tumor to be smaller than 2 cm and low grade (not grade 3). This is often combined with other treatment, e.g., radiation, or intravesical or intravenous chemotherapy. The pelvic lymph nodes can be removed through a laparoscope.
Laser therapy - The laser can be placed into the bladder through a cystoscope using local anesthesia. The light energy can destroy most small bladder tumors, but the recurrence rate is about 10%. Lasers vary in their ability in penetrate into the tissue from about 1 mm to 15 mm.
Hematoporphyrin is a chemical which can make some cancer cells more sensitive to the laser light. It is injected intravenously into the patient and is absorbed by most of the cells in the body. The chemical is quickly washed out of normal cells. Light of a specific color is shown on the cancer cells. The hematoporphyrin within cancer cells is chemically altered by the light and becomes toxic to the cancer cells. This is called photodynamic therapy and is considered to be experimental treatment.
Radiation
External radiation therapy has been used for advanced tumors or as adjuvant therapy following partial cystectomy. Bladder cancer is poorly responsive to radiation therapy, therefore, some institution do not use radiation as adjuvant treatment. Pain on urination, urinary frequency, and diarrhea are complications of radiation, which usually resolve. Iridium 192 implants are occasionally used to reduced local recurrence after partial cystectomy.
Chemotherapy
Drugs placed directly into the bladder can cure or control some patients with tumors which repeatedly recur. Drugs such as thiotepa, Adriamycin and Mitomycin C can be instilled directly into the bladder for one to two hours at a time. Treatment is typically performed weekly for six to eight weeks, followed by monthly treatments for one year. This therapy is effective for about 20 40% of patients. Intravesical BCG therapy is effective treatment for 50% 90% of patients. Each drug is effective against different cancers. If the first drug does not work, a second or third can be tried.
Systemic chemotherapy has been used in experimental programs designed to preserve the bladder. Intravenous chemotherapy can also be used prior to surgery (neoadjuvant chemotherapy) to shrink large tumors and kill small distant metastases that may have formed. Cisplatin, methotrexate, vinblastine, and doxorubicin (Adriamycin) are the most effective drugs.
(Return to Top)
TCC ANALYSIS
Today the debate over treatment still focuses on bladder sparing procedures (transurethral resection or partial cystectomy) versus radical cystectomy. During the past two decades over 100 urologists have reported their experiences with bladder sparing surgery. Most urologists agree that patients who are properly selected and treated survive just as long following conservative surgery as they do following radical cystectomy. But, bladder sparing procedures are utilized on a minority of patients with infiltrating bladder cancers.
Bladder cancer is unique, because of its very high recurrence rate 70% or higher. Many urologists administer chemotherapy after partial cystectomy or TUR to kill remaining tumor cells and reduce the chance for recurrence. There is no firm evidence that this is effective. Recurrence is more likely to arise from cells previously exposed to damaging chemicals, rather than from cancer cells left behind after surgery. If radical surgery is of great benefit anywhere in the body it should be in the bladder, where local recurrence is so high. Radical cystectomy can reduce local recurrence from 70% to about 10%. In spite of this great reduction in local recurrence, radical cystectomy has not displayed a clear survival advantage over bladder sparing operations. This observation also supports the speculation that locally recurrent bladder cancer and locally recurrent breast cancer behave in a similar manner. Promptly treated local recurrence (or local persistence) after conservative surgery does not appear to adversely affect survival.
No scientific trials have been performed to accurately define the type of treatment which is most effective or the types of patients who are best suited for bladder sparing treatment. Several questions remain unanswered. How wide a margin of normal tissue should be removed in a transurethral resection or partial cystectomy? How many failures should be allowed before the patient is treated with cystectomy? Should a third or fourth recurrence be treated with additional surgery or different therapy altogether? Without the benefit of randomized trials these conclusions are only speculation.
In 1993, Thrasher and Crawford of Duke University concluded,"It is probably best to recommend transurethral resection therapy alone to patients in whom more radical therapy is precluded due to medical condition or individual request (emphasis added)."
(Return to Top)
TREATMENT OPTIONS
Stage 0 - The tumor is very superficial involving only the mucosa; includes papillary lesions (Ta) and carcinoma in situ (Tis).
The primary therapy is transurethral resection or fulguration. Chemotherapy or immunological agents can be placed inside the bladder to prevent recurrences. These agents are also used to treat recurrent lesions. Radiation therapy is not effective. Photodynamic therapy is used experimentally for this stage of disease.
Recurrence rates are very high. Only about 30% of patients will have a complete response. The other 70% develop recurrent disease, and another treatment can be attempted. Patients should have bladder examinations every three months for at least two years. The five-year survival rate is over 90%.
Stage A - The tumor penetrates into the submucosa. The treatment is the same as for stage 0.
Stage B - There is superficial muscle invasion, B1 or deep muscle invasion, B2. These tumors should be completed excised with transurethral resection or partial cystectomy. Most urologists recommend 2-cm margins of excision around the tumor. Among patients with high grade tumors the recurrence rate may be as high as 70%. Partial cystectomy may be performed with a margin of less than 2 cm, if necessary to preserve the bladder. Would a margin of 1 cm or less increase local recurrence from 70% to 80%? How risky is this added 10% of local recurrence? Postoperative radiation therapy or drugs placed inside the bladder may improve local control. Patients should have a pelvic lymph node dissection. This can be performed through a laparoscope or as an abdominal operation depending upon the treatment of the bladder tumor. Patients should have bladder examinations every three months for at least two years. If tumor recurs, patients may wish to consider
additional radiation or chemotherapy.
Stage C - The tumor invades into the fat around the bladder. Consider participation in a protocol of preoperative chemotherapy or radiation therapy.
Stage D - The tumor involves adjacent organs or lymph nodes, or distant metastases are present. Treatment is the same as for stage C.
(Return to Top)
MEDICAL RESEARCH
The first cystectomy for bladder cancer was performed in Cologne, Germany in 1887 by Bardenheuer.(1) F. H. Martin performed the first cystectomy in the United States in 1899. Most surgeons avoided the procedure because so many patients died or had serious complications. Young of Johns Hopkins never performed the operation. The earliest cystoscope was invented by Nitze in 1877. It was improved during the 1880's due in part to Edison's incandescent light. Bladder tumors could be avulsed or cauterized with a cystoscope.
Radium was first used to treat bladder tumors by Cleaves of Philadelphia in 1903. A variety of techniques were used to place radon seeds or other sources of radiation directly inside the bladder. The development of high voltage radiation therapy during the 1950's increased the use of external beam radiation.
By the 1940's antibiotics were available, and advances had been made in anesthesia and intravenous therapy. Radical cystectomy again was favored by some urologists. Unfortunately the survival results remained discouraging. By the 1950's, some urologists returned to transurethral resection.
In 1956, Nichols and Marshall of The New York Hospital reviewed their experience from 1932 to 1948 with 112 patients using local excision and fulguration.(2) They concluded that patients with bladder tumors of a low grade and low stage could be successfully treated with bladder-sparing surgery. Patients with high grade or high stage lesions needed more aggressive surgery.
Herr and associates of Memorial Sloan-Kettering Hospital reviewed their experience treating 45 patients with muscle-infiltrating bladder cancer using TUR.(3) (Patients were followed for 3 to 7 years.) Thirty-two patients (71%) developed further bladder cancer. Twenty-one of these were retreated with TUR, and were doing well when last evaluated. Eleven patients developed new bladder cancers -- not recurrences -- that were treated by cystectomy; four of these patients died of bladder cancer. Four patients developed metastatic disease; two had no disease in the bladder. The overall survival of patients free of disease was 82%. There is no evidence that any death was due to the limited initial surgery.
Herr also reviewed the experience of other urologists with transurethral resection (TUR) for bladder cancer.(4) He concluded that TUR was as effective as radical surgery. For patients with cancer that deeply invaded the bladder muscle the five-year survival rates were as follows: TUR: 14 - 57%, Partial cystectomy: 14 - 45%, simple cystectomy: 16 - 40%, and radical cystectomy: 26 - 60%. These figures are not statistically different. Herr concludes his review,"From this review, transurethral resection does not appear to cause metastasis or jeopardize surgical cure."
In 1992, Sweeney and associates from Case Western Reserve summarized the experience from over ten hospitals with partial cystectomy.(5) They found 532 patients who had been treated with partial cystectomy. Local recurrence developed in about 60% (38% - 78%) of patients. But, only 8% of patients treated with partial cystectomy required radical surgical treatment later. The majority were treated with repeat transurethral resection or fulguration. Patient survival was determined by both the grade of the tumor and the stage of the disease. The type of treatment did not affect survival.
Consider the survival of patients who develop recurrence following a conservative operation -- the major theme of this book. Faysal and Freiha from Stanford University treated 117 patients with partial cystectomy.(6) Recurrences developed in 78% of patients. About half of these patients developed recurrences which were of a higher stage than their first cancer. Forty percent developed recurrences which were of a higher grade than their first cancer. The authors do not mention their follow-up schedule and state that information was obtained from the California Tumor Registry. Patients may not have been seen every three months, as many urologists now recommend. About 49% of these patients lived for five years following treatment of their recurrence. The survival rate was higher for patients who were ultimately treated with cystectomy.
Investigators from the Cleveland Clinic and the University of Iowa have reported favorable experience with bladder-sparing surgery.(7),(8) Investigators at the Massachusetts General Hospital have designed a protocol which combines transurethral resection, systemic chemotherapy and external beam radiation.(9)
References
1. Murphy LJT. The History of Urology. Charles C. Thomas: Springfield, Ill. 1972.
2. Nichols JA, Marshall VF. The treatment of bladder carcinoma by local excision and fulguration. Cancer 1956; 9:559-65.
3. Herr HW. Conservative management of muscle-infiltrating bladder cancer: prospective experience. J Urol 1987; 138:1162-1163.
4. Herr HW. Transurethral resection in regionally advanced bladder cancer. Urol Clin Nor Am 1992; 19:695-700.
5. Sweeney P, Kursh ED, Resnick MI. Partial cystectomy. Urol Clin Nor Am 1992; 19:701-711.
6. Faysal MH, Freiha FS. Evaluation of partial cystectomy for carcinoma of bladder. Urology 1979; 14:352-356.
7. Novick AC, Stewart BH. Partial cystectomy in the treatment of primary and secondary carcinoma of the bladder. J Urol 1976; 116:570-4.
8. Novick AC, Stewart BH. Partial cystectomy in the treatment of primary and secondary carcinoma of the bladder. J Urol 1976;116:570-4.
9. Kaufman DS, Shipley WU, Griffin PP, et al. Selective bladder preservation by combination treatment of invasive bladder cancer. N Engl J Med 1993; 329:1377-82.
(Return to Top)
Medical Research since 1995
Since 1995, bladder-sparing treatment has become available at several major cancer centers. Treatment usually involves transurethral resection (TUR) of the bladder, radiation therapy and chemotherapy. Survival following conservative treatment appears comparable to that of radical surgery (cystectomy). But, I am aware of no scientific trials that have confirmed this. Overall 5-year survival rates of about 50 to 60 percent have been reported.
Combination treatment is complex and expensive. It usually requires more than 6 months to complete. The side effects of chemotherapy can be severe. In two prominent studies 4 percent of patients died from the chemotherapy. Advances in reconstructive surgery have improved the quality of life for patients who elect to have their bladder removed. Radical cystectomy is still the standard treatment for patients with invasive bladder cancer.
Limited Surgery Alone
Regrettably, the study of bladder-sparing treatment has not progressed in the orderly fashion that occurred in the study of breast cancer. (See Chapter 1) Conservative surgery alone has received little attention. M. Laufer of Johns Hopkins Oncology Center in Baltimore has pointed out that surgery alone (without radiation or chemotherapy) has been "incompletely evaluated" due to the small number of patients studied. However, he concluded that the outcome of treatment as measured by preservation of the bladder and overall survival is "not dissimilar to" the results of radical surgery.(10) In 2001, H.W. Herr and associates of Memorial Sloan-Kettering Cancer Center reported their experience with 99 patients whose initial treatment was aggressive TUR alone.(11) After 10 years, Herr concluded that surgery alone was successful in patients whose tumor could be completely removed by surgery. This is an opinion which Herr has maintained for many years. (See above.)
Studies of Combination Treatment
Since 1995, many articles have been written on bladder-sparing treatment. Most of these studies have involved the combined use of surgery, radiation therapy, and chemotherapy. In 2000, H. L. Kim and G.D. Steinberg of the University of Chicago published a good review of combination therapy for bladder cancer.(12)
C. N. Sternberg and associates from the San Raffaele Scientific Institute in Rome treated 87 patients with preoperative chemotherapy.(13) Fifty-five of these patients responded to chemotherapy and were then treated with bladder-sparing surgery. The five-year survival rate of these patients was 71 percent. The authors support bladder-sparing surgery for patients who respond to chemotherapy and recommend additional scientific study.
H. W. Herr and associates from the Memorial Sloan-Kettering Cancer Center treated 111 patients with preoperative chemotherapy.(14) Sixty patients had no evidence of cancer after the treatment; nevertheless, 17 of them decided to have a cystectomy. The remaining 43 patients underwent bladder-sparing surgery. Twenty-four of these patients (56 percent) were treated for recurrent cancer in the bladder. Ten years after treatment 32 patients (74 percent) were alive and 25 had a functioning bladder. Among the 17 patients who elected to have a cystectomy, 11 (65 percent) were alive at ten years. In this study patients who were treated with bladder-sparing surgery appeared to live longer than those treated with cystectomy. Compare the ten-year survival rates of 74 percent (bladder-sparing surgery) vs. 65 percent (cystectomy).
J. E. Montie of the University of Michigan, Ann Arbor, reviewed the literature on bladder-sparing surgery.(15) He said that about 50 percent of patients developed recurrent cancer in the bladder and that about half of these recurrences invaded the muscle of the bladder. Montie went on to call these recurrences "an additional source of metastatic disease and death." He supported this conclusion by referring to the study by Herr above - a study which found no additional deaths among patients treated conservatively.
Montie also referred to a paper by William Tester and associates from the Albert Einstein Cancer Center in Philadelphia.(16) They treated 91 patients with invasive bladder cancer using preoperative chemotherapy and radiation. The authors concluded that, ". . . bladder preservation can be achieved in the majority of patients, and that overall survival is similar to that reported with aggressive surgical approaches."
Montie found no evidence of improved survival among patients treated with cystectomy. Nevertheless, he concluded that cystectomy was "optimal therapy" for bladder cancer. Montie presented no scientific evidence which suggested that conservative surgery was a threat to survival. His negative opinion of conservative surgery was based, in part, on 2 studies which, in fact, supported conservative surgery. Montie's findings support the views presented here.
Texas Cancer Center Treatment Analysis
I believe that conservative treatment will become more popular and that the side effects of bladder preservation will decline as doctors refine, reduce or eliminate their use of radiation and chemotherapy. For no other cancer has organ-sparing treatment involved such an aggressive use of adjuvant radiation and chemotherapy.
All available medical evidence continues to support the increased use of bladder-sparing treatment. I believe that many urologists continue to have a bias against bladder-sparing treatment, just as breast cancer surgeons had a bias against breast-sparing treatment. Bladder cancer has a very high rate of local recurrence and there continues to be no evidence that local recurrence is a threat to overall survival. The Texas Cancer Center supports the position of the NSABP that local recurrence is a marker for distant metastasis, not its cause. Promptly-treated local recurrence does not spread.
Medical References since 1995
10. Laufer M. Transurethral resection and partial cystectomy for invasive bladder cancer. Semin Urol Oncol 18:296-299, 2000.
11. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 19:89-93, 2001.
12. Kim HL, Steinberg GD. The current status of bladder preservation in the treatment of muscle invasive bladder cancer. J Urol 164:627-632, 2000.
13. Sternberg CN, Pansadoro V, Calabro F, Marini L, van Rijn A, Carli PD, and others. Neo-adjuvant chemotherapy and bladder preservation in locally advanced transitional cell carcinoma of the bladder. Ann Oncol 10:1301-5, 1999.
14. Herr HW, Bajorin DF, Scher HI. Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. J Clin Oncol 16:1298-301, 1998.
15. Montie JE. Against bladder sparing surgery. J Urol 162:452-7, 1999.
16. Tester W, Caplan R, Heaney J, and others. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: Results of Radiation Therapy Oncology Group Phase II Trail 8892. J Clin Oncol 14:119-126, 1996.
(Return to Top)
The Texas Cancer Center gratefully welcomes contributions from all those 
