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BLADDER CANCER THERAPY
Interavesical Therapy
Unfortunately, when TCC is treated by TUR alone, bladder cancer may reappear in up to 90% of all patients. Therefore, other treatment methods have been developed to decrease the likelihood of cancer recurrence. Intravesical therapy includes both chemotherapy (chemical therapy) and immunotherapy (therapy by immune system stimulation). During this procedure, the medication (chemotherapeutic drug or immune vaccine) is placed intravesically - that is, directly within the bladder. Intravesical therapy concentrates the medication at the tumor site to reduce the survival of any tumor tissue that is overlooked after TUR. The most frequently used drugs for intravesical therapy are the immunotherapeutic agent Bacillus Calmette-GuÈrin (BCG), thiotepa, mitomycin C, doxorubicin hydrochloride, and epirubicin.
Bacillus Calmette-GuÈrin (BCG)
BCG vaccine is a nonspecific immune stimulant. BCG acts by binding to the bladder tissue and starting an immune response that hampers tumor growth. During treatment, BCG is dissolved in normal saline (salt solution). The solution is instilled (administered by slow drip) into the bladder through a urethral catheter for 2 hours weekly for 6 or more weeks. BCG is a very effective form of intravesical therapy, especially for carcinoma in situ (CIS, TIS), which can be aggressive despite its surface location on the bladder wall. BCG decreases the frequency of tumor recurrence in over half of all CIS patients, and it reduces invasive potential in individuals with high-grade tumors. BCG therapy may cause side effects such as bladder irritation, hematuria, flu-like symptoms and, rarely, fever or sepsis (infection). However, most patients are able to tolerate BCG therapy, and flu and fever symptoms can be reduced by simultaneous use of the antituberculosis drug isoniazid (INH).
As previously noted, the most common intravesical chemotherapeutic drugs are thiotepa, mitomycin C, doxorubicin hydrochloride, and epirubicin.
Thiotepa
Thiotepa (triethylenethiophosphoramide) is an alkylating agent that is chemically related to nitrogen mustard. It stops cancer growth by causing cross-links between vital nucleic acids and proteins within the tumor. The usual dose of thiotepa is 30 to 60 mg in distilled water weekly for 6 weeks, followed by monthly treatments. Thiotepa therapy alone produces complete responses in only one third of patients. Thiotepa therapy after TUR increases disease-free survival at 12- and 20-month periods.
Mitomycin C
Mitomycin C, like thiotepa, also causes cross-links in substances that are essential for tumor growth. It may be beneficial for patients who have failed thiotepa therapy, and, because it is not readily absorbed through the bladder, bodily side effects are uncommon (skin rash, especially of the palms, has been noted in some patients). The customary dose of mitomycin is 20 to 60 mg weekly for 8 weeks.
Doxorubicin hydrochloride
Doxorubicin hydrochloride (Adriamycin®) is a toxic antibiotic that disrupts tumor cell function. It is given in 30 to 90 mg doses over different time frames. Some studies have shown increased tumor-free survival with doxorubicin at 18 months of follow-up. Doxorubicin hydrochloride is not as well absorbed through the bladder and is less toxic to the system than thiotepa.
Epirubicin
Epirubicin (4'-epidoxorubicin) is a new drug that is related to doxorubicin and has similar effects upon tumor growth. Dosages range from 30 to 80 mg weekly for up to 8 weeks.
People who receive chemotherapy with thiotepa, mitomycin C, doxorubicin, or epirubicin may experience chemical cystitis (chemical-caused irritation during urination). In addition, thiotepa can cause myelosuppression (decreased bone marrow production of blood cells and platelets - blood clotting factors) and leukopenia (reduced number of white blood cells, WBCs). Therefore, numbers of WBCs and platelets should be monitored during thiotepa treatment.
Unfortunately, long-term results are not very encouraging for intravesical chemotherapy. Many studies show that the rate of tumor reappearance after 5 or more years is the same or higher in treated versus untreated patients. In addition, intravesical chemotherapy apparently has no clear advantages for preventing cancer invasion, lengthening time to appearance of metastasis, or reducing bladder cancer death rates. The only significant reported benefit is improved disease-free survival. Therefore, the causes of failed intravesical chemotherapies are now being investigated. Combination chemotherapy may be a more effective and promising alternative; for example, mitomycin C plus doxorubicin; epirubicin plus a2b-interferon.
Intravesical therapy (either immunotherapy with BCG or chemotherapy) is recommended for most patients with superficial bladder cancer. This includes patients with:
· Papillary (wart-like) tumors that are multiple, diffuse (scattered), or poorly differentiated (nonspecialized)
· Carcinoma in situ (CIS, TIS)
· Any T1 tumor (tumor that has invaded connective tissue)
· Recurrent tumor within 1 year of therapy
· Urine cytology that is positive for tumor cells after tumor surgery
It should be noted that patients with CIS involving von Brunn's nests -- that is, pockets of cells that extend more deeply below the bladder surface -- will have tumor cells that are unexposed and, consequently, unaffected by intravesical therapy. Thus, intravesical therapy is not suitable for individuals with von Brunn's CIS (see also Transitional Cell Carcinoma).
A number of new drugs and techniques have been investigated for use as intravesical therapy. Such options may be especially helpful for patients who are unresponsive to BCG or other agents. They include interferons, immune system stimulants and modulators, photodynamic therapy with laser light, and gene therapy.
· Interferons are naturally occurring compounds that exert many beneficial anticancer effects, such as the slowing of tumor cell growth and antiviral activity. The recombinant interferon a2b (rINFa-2b) is a particularly good second-line option for patients who do not tolerate or respond to BCG or chemotherapy.
· Bropirimine is an oral immunomodulator that causes the body to produce interferon as well as other beneficial cancer-fighting substances (for example, interleukin-1, tumor necrosis factor, cytokines, etc.).
· Keyhole-limpet hemocyanin (KLH), a shellfish-based compound, is a nonspecific immune system stimulant. KHL causes few side effects and may prove advantageous for the prevention of recurrent tumors.
· Photodynamic Therapy (PDT) is a two-step process that selectively destroys the rapidly dividing cells of bladder cancers. PDT is begun by intravenous treatment with a photosensitizer (for example, the chemical Photofrin), which makes the bladder lining tissue light-sensitive. Next, "intrevesical activation" of the bladder lining is achieved by laser therapy with visible light. PDT causes cancer cell destruction and vascular damage; however, PDT also may produce severe side effects, such as cystitis-like syndrome ("post-PDT syndrome"), bladder contracture (shrinkage), and prolonged sensitivity to sunlight.
· Gene Therapy includes treatments that use genes to (1) correct faulty genetic information or (2) selectively destroy cancerous tissue. In the second category, vaccinia virus (a pox virus) has been genetically modified to express an antitumor response in the bladder.
Staging this disease
Once the physician has determined that a tumor exists, the next step is to clarify the tumor's status. Several questions will have to be answered: Is the tumor large or small? Does it lie within the lining of the bladder or has it extended into the surrounding tissue? Has the tumor spread to nearby lymph nodes? Has the tumor metastasized to distant sites within the body?
Fortunately, a number of systems have been developed to answer these questions. The most common of these -- the TNM (tumor, node, metastasis) system -- allows tumors to be classified, or "staged," according to their overall characteristics. A biopsy is removed and sent to a histopathologist for examination under a microscope. The pathologist then assigns a stage and a grade to the tissue sample.
The stage refers to the physical location of the tumor within the bladder or, more specifically, the tumor's depth of penetration. In general, tumor stage is confined to one of two categories: (1) superficial, surface tumors, or (2) invasive, deep-spreading tumors. Superficial tumors affect only the bladder lining. They grow up and out from the lining tissue and extend into the bladder's hollow cavity. Invasive tumors grow down into the deeper layers of bladder tissue, and they may involve surrounding muscle, fat, and/or nearby organs. Invasive tumors are more dangerous than superficial tumors, since they are more likely to metastasize.
The grade is an estimate of the speed of tumor growth as suggested by cell features seen under a microscope. Most systems are based upon the degree of tumor cell anaplasia - that is, the loss of cellular "differentiation," the distinguishing characteristics of a cell. The World Health Organization (WHO) grading system groups transitional cell carcinomas (TCCs) into three grades that correspond to well-, moderately, and poorly differentiated cells. The International Union Against Cancer (UICC) has devised a four-grade system that considers Grade 1 tumors to be well-differentiated, Grade 2 to be moderately differentiated, and Grades 3 or 4 to be poorly differentiated. Both systems are widely used and can be summarized as follows:
· Grade 1 (well-differentiated)
· Grade 2 (moderately differentiated)
· Grade 3 or Grade 4 (poorly differentiated)
There is a continuing debate about the classification of benign bladder lesions known as papillomas. The WHO defines papilloma as a single papillary (wart-like) growth with 8 or less cell layers in normal-looking surface tissue. By contrast, many pathologists and urologists classify papilloma as a Grade 1 TCC because of its tendency to recur and not to invade muscle.
There is a strong correlation between tumor stage and tumor grade. Nearly all superficial tumors are low grade; that is, they are Grade 1 tumors, with cells that are distinctly specialized and well-differentiated, whereas nearly all muscle-invasive tumors are high grade; that is, they are Grade 3 or 4 tumors, with cells that are nonspecialized and poorly differentiated. More importantly, there is a strong correlation between tumor stage and prognosis (the probable outcome of a disease), with superficial tumors having the most chance of a favorable result.
What are the treatments?
The treatment of bladder cancer depends upon many factors. The most important of these factors are the type of tumor that is present and its stage. (see also Bladder Cancer Staging and Types of Bladder Cancer).
SURGICAL THERAPY
Bladder cancers that are no longer confined to the surface lining and have grown into surrounding tissue usually require surgical therapy. Specifically, Stage T2 to T3a tumors—that is, tumors that have invaded the muscle or fatty tissue around the bladder—need surgical management. In men, a standard surgical procedure is cystoprostatectomy (removal of the bladder and prostate) with pelvic lymphadenectomy (removal of the lymph nodes within the hip cavity). Bladder surgery, which usually involves removal of the seminal vesicles (semen-conducting tubes), can be performed in a manner that preserves sexual function in some men. In addition, new surgical methods of urinary diversion (re-routing of urine through a surgical channel) may eliminate the need for an external urinary appliance.
Radical Cystectomy
In women with T2 to T3a tumors, a standard surgical procedure is radical cystectomy (cutting away of the entire bladder and associated tissues) with pelvic lymphadenectomy. Radical cystectomy in women includes removal of the uterus (womb), tubes, ovaries, anterior vaginal wall (front of the birth canal), and urethra (the tube that passes urine from the bladder out of the body). Preoperative radiation therapy may have some merit when combined with bladder surgery, although radiation therapy alone usually is unsuccessful.
Segmental Cystectomy
Segmental cystectomy (partial removal of the bladder)—a bladder-preserving or "salvage" form of surgery—is appropriate only in a limited selection of male or female patients (for example, patients with squamous cell carcinomas or adenocarcinomas that arise high in the bladder dome). When segmental cystectomy is performed, it may be preceded by radiation therapy (see also Radiation Therapy).
Urinary Tract Diversion
Until recently, most bladder cancer patients who underwent cystectomy (bladder removal) needed an ostomy (surgical creation of an artificial opening) and an external bag to collect their urine. Now, reconstructive surgical methods have been developed to replace the cancerous bladder. The continent urinary reservoir is the newest form of urinary diversion. With this technique, a piece of colon (large intestine) is removed and used to form an internal pouch to store urine. The pouch is specially refashioned to prevent back-up of urine into the ureters (one of two tubes that pass urine out of the kidneys and into the bladder) and kidneys. The patient—whether male or female—can urinate as before, without the need for an external bag or collection device. The urinary reservoir procedure is associated with some complications, such as bowel (intestine) obstruction, blood clots, pneumonia (lung inflammation), ureteral reflux (back-flow), and ureteral blockage.
Ileal Conduit
The ileal conduit is a small urine reservoir that is surgically created from a small piece of the patient's bowel. During this procedure, the ureters are attached to one end of the bowel piece; the other end is brought out onto the surface of the body to make a stoma. The patient then attaches an external, urine-collecting bag to the stoma. This bag needs to be worn at all times. Complications of the ileal conduit procedure include bowel obstruction, urinary tract infection (UTI), blood clots, pneumonia, upper urinary tract damage, and skin breakdown around the stoma.
Radiation Therapy - Outside of the United States, radiation therapy (also known as radiotherapy) often is used as a primary (singular) treatment for invasive bladder cancer. Yet, in America, primary radiation therapy usually is reserved for people who may not be good candidates for bladder surgery because of age or certain medical problems. Primary therapy generally involves a radiation dose of 6,000 to 7,000 rad to the bladder, with or without corresponding lymph node treatment. High-dose, external beam radiation therapy may be an alternative to bladder surgery in patients with stage T2 to T3 muscle-invading cancers. Radiation therapy has no role in the management of carcinoma in situ (CIS, TIS). However, 5-year survival rates are much lower in radiation-treated patients versus patients who undergo surgical therapy. And, unfortunately, local reappearance of bladder cancer occurs in up to one-half of all individuals who receive radiation therapy. Yet people who experience complete tumor regression after radiation therapy tend to do well. There can be significant side effects from high-dose external beam radiation therapy, including radiation cystitis (symptoms of irritation, incontinence, bloody urine, and fibrosis, a buildup of fibrous tissue), proctitis (inflammation of the rectum), impotence, and skin reactions.
Preoperative Radiation Therapy
Preoperative radiation therapy is another strategy that has been used for bladder cancer treatment. The theory is that radiation exposure will "sterilize" tumor outgrowths, regional lymph node metastases, and any tumor cells that are spread during the process of cystectomy (bladder removal). Radiation therapy also is used to shrink the tumor before surgery. Preoperative radiation sometimes is given in a short-course schedule of 2,000 CGy over a 1-week period. But survival results from clinical studies have been conflicting. In addition, preoperative radiation may cause a significant delay in the performance of cystectomy. Therefore, there is a tendency for American physicians to omit radiotherapy prior to cystectomy in patients with invasive bladder cancer. Exceptions to this include patients with invasive squamous cell carcinoma (SCC) or bilharzial bladder cancer.
Systemic Chemotherapy
Many individuals with late-stage bladder tumor(s) and/or metastases have a poor prognosis. Therefore, researchers have begun a number of clinical trials to test the effectiveness of systemic (in the vein) chemotherapy with multiple drugs. In particular, combinations of agents such as cisplatin, methotrexate, and vinblastine, with or without doxorubicin (CMV or M-VAC), have produced some encouraging responses in late-stage patients. In addition, the combination of cisplatin, cyclophosphamide, and doxorubicin (CISCA) has shown some activity, although the responses have not been as great as those reported for CMV or M-VAC treatments. In metastatic bladder cancer, other chemotherapeutic agents that have produced some benefits are: paclitaxel, ifosfamide, gallium nitrate, and gemcitabine. Whenever possible, individuals should be encouraged to participate in such trials. Multi-agent chemotherapeutic trials for metastatic bladder cancer have produced response rates of up to 70%, and survival times may be increased.
In persons with inoperable bladder cancer, the focus of care is palliation (relief) of symptoms. Large, late-stage tumors may cause frequent, painful, and bloody urination during the night and day. Decaying tissue within the tumor also may be a constant source of infection. Therefore, urinary tract diversion in such individuals may spare them the suffering and sleeplessness of persistent, agonizing urination.
Unfortunately, when TCC is treated by TUR alone, bladder cancer may reappear in up to 90% of all patients. Therefore, other treatment methods have been developed to decrease the likelihood of cancer recurrence. Intravesical therapy includes both chemotherapy (chemical therapy) and immunotherapy (therapy by immune system stimulation). During this procedure, the medication (chemotherapeutic drug or immune vaccine) is placed intravesically - that is, directly within the bladder. Intravesical therapy concentrates the medication at the tumor site to reduce the survival of any tumor tissue that is overlooked after TUR. The most frequently used drugs for intravesical therapy are the immunotherapeutic agent Bacillus Calmette-GuÈrin (BCG), thiotepa, mitomycin C, doxorubicin hydrochloride, and epirubicin.
Bacillus Calmette-GuÈrin (BCG)
BCG vaccine is a nonspecific immune stimulant. BCG acts by binding to the bladder tissue and starting an immune response that hampers tumor growth. During treatment, BCG is dissolved in normal saline (salt solution). The solution is instilled (administered by slow drip) into the bladder through a urethral catheter for 2 hours weekly for 6 or more weeks. BCG is a very effective form of intravesical therapy, especially for carcinoma in situ (CIS, TIS), which can be aggressive despite its surface location on the bladder wall. BCG decreases the frequency of tumor recurrence in over half of all CIS patients, and it reduces invasive potential in individuals with high-grade tumors. BCG therapy may cause side effects such as bladder irritation, hematuria, flu-like symptoms and, rarely, fever or sepsis (infection). However, most patients are able to tolerate BCG therapy, and flu and fever symptoms can be reduced by simultaneous use of the antituberculosis drug isoniazid (INH).
As previously noted, the most common intravesical chemotherapeutic drugs are thiotepa, mitomycin C, doxorubicin hydrochloride, and epirubicin.
Thiotepa
Thiotepa (triethylenethiophosphoramide) is an alkylating agent that is chemically related to nitrogen mustard. It stops cancer growth by causing cross-links between vital nucleic acids and proteins within the tumor. The usual dose of thiotepa is 30 to 60 mg in distilled water weekly for 6 weeks, followed by monthly treatments. Thiotepa therapy alone produces complete responses in only one third of patients. Thiotepa therapy after TUR increases disease-free survival at 12- and 20-month periods.
Mitomycin C
Mitomycin C, like thiotepa, also causes cross-links in substances that are essential for tumor growth. It may be beneficial for patients who have failed thiotepa therapy, and, because it is not readily absorbed through the bladder, bodily side effects are uncommon (skin rash, especially of the palms, has been noted in some patients). The customary dose of mitomycin is 20 to 60 mg weekly for 8 weeks.
Doxorubicin hydrochloride
Doxorubicin hydrochloride (Adriamycin®) is a toxic antibiotic that disrupts tumor cell function. It is given in 30 to 90 mg doses over different time frames. Some studies have shown increased tumor-free survival with doxorubicin at 18 months of follow-up. Doxorubicin hydrochloride is not as well absorbed through the bladder and is less toxic to the system than thiotepa.
Epirubicin
Epirubicin (4'-epidoxorubicin) is a new drug that is related to doxorubicin and has similar effects upon tumor growth. Dosages range from 30 to 80 mg weekly for up to 8 weeks.
People who receive chemotherapy with thiotepa, mitomycin C, doxorubicin, or epirubicin may experience chemical cystitis (chemical-caused irritation during urination). In addition, thiotepa can cause myelosuppression (decreased bone marrow production of blood cells and platelets - blood clotting factors) and leukopenia (reduced number of white blood cells, WBCs). Therefore, numbers of WBCs and platelets should be monitored during thiotepa treatment.
Unfortunately, long-term results are not very encouraging for intravesical chemotherapy. Many studies show that the rate of tumor reappearance after 5 or more years is the same or higher in treated versus untreated patients. In addition, intravesical chemotherapy apparently has no clear advantages for preventing cancer invasion, lengthening time to appearance of metastasis, or reducing bladder cancer death rates. The only significant reported benefit is improved disease-free survival. Therefore, the causes of failed intravesical chemotherapies are now being investigated. Combination chemotherapy may be a more effective and promising alternative; for example, mitomycin C plus doxorubicin; epirubicin plus a2b-interferon.
Intravesical therapy (either immunotherapy with BCG or chemotherapy) is recommended for most patients with superficial bladder cancer. This includes patients with:
· Papillary (wart-like) tumors that are multiple, diffuse (scattered), or poorly differentiated (nonspecialized)
· Carcinoma in situ (CIS, TIS)
· Any T1 tumor (tumor that has invaded connective tissue)
· Recurrent tumor within 1 year of therapy
· Urine cytology that is positive for tumor cells after tumor surgery
It should be noted that patients with CIS involving von Brunn's nests -- that is, pockets of cells that extend more deeply below the bladder surface -- will have tumor cells that are unexposed and, consequently, unaffected by intravesical therapy. Thus, intravesical therapy is not suitable for individuals with von Brunn's CIS (see also Transitional Cell Carcinoma).
A number of new drugs and techniques have been investigated for use as intravesical therapy. Such options may be especially helpful for patients who are unresponsive to BCG or other agents. They include interferons, immune system stimulants and modulators, photodynamic therapy with laser light, and gene therapy.
· Interferons are naturally occurring compounds that exert many beneficial anticancer effects, such as the slowing of tumor cell growth and antiviral activity. The recombinant interferon a2b (rINFa-2b) is a particularly good second-line option for patients who do not tolerate or respond to BCG or chemotherapy.
· Bropirimine is an oral immunomodulator that causes the body to produce interferon as well as other beneficial cancer-fighting substances (for example, interleukin-1, tumor necrosis factor, cytokines, etc.).
· Keyhole-limpet hemocyanin (KLH), a shellfish-based compound, is a nonspecific immune system stimulant. KHL causes few side effects and may prove advantageous for the prevention of recurrent tumors.
· Photodynamic Therapy (PDT) is a two-step process that selectively destroys the rapidly dividing cells of bladder cancers. PDT is begun by intravenous treatment with a photosensitizer (for example, the chemical Photofrin), which makes the bladder lining tissue light-sensitive. Next, "intrevesical activation" of the bladder lining is achieved by laser therapy with visible light. PDT causes cancer cell destruction and vascular damage; however, PDT also may produce severe side effects, such as cystitis-like syndrome ("post-PDT syndrome"), bladder contracture (shrinkage), and prolonged sensitivity to sunlight.
· Gene Therapy includes treatments that use genes to (1) correct faulty genetic information or (2) selectively destroy cancerous tissue. In the second category, vaccinia virus (a pox virus) has been genetically modified to express an antitumor response in the bladder.
Staging this disease
Once the physician has determined that a tumor exists, the next step is to clarify the tumor's status. Several questions will have to be answered: Is the tumor large or small? Does it lie within the lining of the bladder or has it extended into the surrounding tissue? Has the tumor spread to nearby lymph nodes? Has the tumor metastasized to distant sites within the body?
Fortunately, a number of systems have been developed to answer these questions. The most common of these -- the TNM (tumor, node, metastasis) system -- allows tumors to be classified, or "staged," according to their overall characteristics. A biopsy is removed and sent to a histopathologist for examination under a microscope. The pathologist then assigns a stage and a grade to the tissue sample.
The stage refers to the physical location of the tumor within the bladder or, more specifically, the tumor's depth of penetration. In general, tumor stage is confined to one of two categories: (1) superficial, surface tumors, or (2) invasive, deep-spreading tumors. Superficial tumors affect only the bladder lining. They grow up and out from the lining tissue and extend into the bladder's hollow cavity. Invasive tumors grow down into the deeper layers of bladder tissue, and they may involve surrounding muscle, fat, and/or nearby organs. Invasive tumors are more dangerous than superficial tumors, since they are more likely to metastasize.
The grade is an estimate of the speed of tumor growth as suggested by cell features seen under a microscope. Most systems are based upon the degree of tumor cell anaplasia - that is, the loss of cellular "differentiation," the distinguishing characteristics of a cell. The World Health Organization (WHO) grading system groups transitional cell carcinomas (TCCs) into three grades that correspond to well-, moderately, and poorly differentiated cells. The International Union Against Cancer (UICC) has devised a four-grade system that considers Grade 1 tumors to be well-differentiated, Grade 2 to be moderately differentiated, and Grades 3 or 4 to be poorly differentiated. Both systems are widely used and can be summarized as follows:
· Grade 1 (well-differentiated)
· Grade 2 (moderately differentiated)
· Grade 3 or Grade 4 (poorly differentiated)
There is a continuing debate about the classification of benign bladder lesions known as papillomas. The WHO defines papilloma as a single papillary (wart-like) growth with 8 or less cell layers in normal-looking surface tissue. By contrast, many pathologists and urologists classify papilloma as a Grade 1 TCC because of its tendency to recur and not to invade muscle.
There is a strong correlation between tumor stage and tumor grade. Nearly all superficial tumors are low grade; that is, they are Grade 1 tumors, with cells that are distinctly specialized and well-differentiated, whereas nearly all muscle-invasive tumors are high grade; that is, they are Grade 3 or 4 tumors, with cells that are nonspecialized and poorly differentiated. More importantly, there is a strong correlation between tumor stage and prognosis (the probable outcome of a disease), with superficial tumors having the most chance of a favorable result.
What are the treatments?
The treatment of bladder cancer depends upon many factors. The most important of these factors are the type of tumor that is present and its stage. (see also Bladder Cancer Staging and Types of Bladder Cancer).
SURGICAL THERAPY
Bladder cancers that are no longer confined to the surface lining and have grown into surrounding tissue usually require surgical therapy. Specifically, Stage T2 to T3a tumors—that is, tumors that have invaded the muscle or fatty tissue around the bladder—need surgical management. In men, a standard surgical procedure is cystoprostatectomy (removal of the bladder and prostate) with pelvic lymphadenectomy (removal of the lymph nodes within the hip cavity). Bladder surgery, which usually involves removal of the seminal vesicles (semen-conducting tubes), can be performed in a manner that preserves sexual function in some men. In addition, new surgical methods of urinary diversion (re-routing of urine through a surgical channel) may eliminate the need for an external urinary appliance.
Radical Cystectomy
In women with T2 to T3a tumors, a standard surgical procedure is radical cystectomy (cutting away of the entire bladder and associated tissues) with pelvic lymphadenectomy. Radical cystectomy in women includes removal of the uterus (womb), tubes, ovaries, anterior vaginal wall (front of the birth canal), and urethra (the tube that passes urine from the bladder out of the body). Preoperative radiation therapy may have some merit when combined with bladder surgery, although radiation therapy alone usually is unsuccessful.
Segmental Cystectomy
Segmental cystectomy (partial removal of the bladder)—a bladder-preserving or "salvage" form of surgery—is appropriate only in a limited selection of male or female patients (for example, patients with squamous cell carcinomas or adenocarcinomas that arise high in the bladder dome). When segmental cystectomy is performed, it may be preceded by radiation therapy (see also Radiation Therapy).
Urinary Tract Diversion
Until recently, most bladder cancer patients who underwent cystectomy (bladder removal) needed an ostomy (surgical creation of an artificial opening) and an external bag to collect their urine. Now, reconstructive surgical methods have been developed to replace the cancerous bladder. The continent urinary reservoir is the newest form of urinary diversion. With this technique, a piece of colon (large intestine) is removed and used to form an internal pouch to store urine. The pouch is specially refashioned to prevent back-up of urine into the ureters (one of two tubes that pass urine out of the kidneys and into the bladder) and kidneys. The patient—whether male or female—can urinate as before, without the need for an external bag or collection device. The urinary reservoir procedure is associated with some complications, such as bowel (intestine) obstruction, blood clots, pneumonia (lung inflammation), ureteral reflux (back-flow), and ureteral blockage.
Ileal Conduit
The ileal conduit is a small urine reservoir that is surgically created from a small piece of the patient's bowel. During this procedure, the ureters are attached to one end of the bowel piece; the other end is brought out onto the surface of the body to make a stoma. The patient then attaches an external, urine-collecting bag to the stoma. This bag needs to be worn at all times. Complications of the ileal conduit procedure include bowel obstruction, urinary tract infection (UTI), blood clots, pneumonia, upper urinary tract damage, and skin breakdown around the stoma.
Radiation Therapy - Outside of the United States, radiation therapy (also known as radiotherapy) often is used as a primary (singular) treatment for invasive bladder cancer. Yet, in America, primary radiation therapy usually is reserved for people who may not be good candidates for bladder surgery because of age or certain medical problems. Primary therapy generally involves a radiation dose of 6,000 to 7,000 rad to the bladder, with or without corresponding lymph node treatment. High-dose, external beam radiation therapy may be an alternative to bladder surgery in patients with stage T2 to T3 muscle-invading cancers. Radiation therapy has no role in the management of carcinoma in situ (CIS, TIS). However, 5-year survival rates are much lower in radiation-treated patients versus patients who undergo surgical therapy. And, unfortunately, local reappearance of bladder cancer occurs in up to one-half of all individuals who receive radiation therapy. Yet people who experience complete tumor regression after radiation therapy tend to do well. There can be significant side effects from high-dose external beam radiation therapy, including radiation cystitis (symptoms of irritation, incontinence, bloody urine, and fibrosis, a buildup of fibrous tissue), proctitis (inflammation of the rectum), impotence, and skin reactions.
Preoperative Radiation Therapy
Preoperative radiation therapy is another strategy that has been used for bladder cancer treatment. The theory is that radiation exposure will "sterilize" tumor outgrowths, regional lymph node metastases, and any tumor cells that are spread during the process of cystectomy (bladder removal). Radiation therapy also is used to shrink the tumor before surgery. Preoperative radiation sometimes is given in a short-course schedule of 2,000 CGy over a 1-week period. But survival results from clinical studies have been conflicting. In addition, preoperative radiation may cause a significant delay in the performance of cystectomy. Therefore, there is a tendency for American physicians to omit radiotherapy prior to cystectomy in patients with invasive bladder cancer. Exceptions to this include patients with invasive squamous cell carcinoma (SCC) or bilharzial bladder cancer.
Systemic Chemotherapy
Many individuals with late-stage bladder tumor(s) and/or metastases have a poor prognosis. Therefore, researchers have begun a number of clinical trials to test the effectiveness of systemic (in the vein) chemotherapy with multiple drugs. In particular, combinations of agents such as cisplatin, methotrexate, and vinblastine, with or without doxorubicin (CMV or M-VAC), have produced some encouraging responses in late-stage patients. In addition, the combination of cisplatin, cyclophosphamide, and doxorubicin (CISCA) has shown some activity, although the responses have not been as great as those reported for CMV or M-VAC treatments. In metastatic bladder cancer, other chemotherapeutic agents that have produced some benefits are: paclitaxel, ifosfamide, gallium nitrate, and gemcitabine. Whenever possible, individuals should be encouraged to participate in such trials. Multi-agent chemotherapeutic trials for metastatic bladder cancer have produced response rates of up to 70%, and survival times may be increased.
In persons with inoperable bladder cancer, the focus of care is palliation (relief) of symptoms. Large, late-stage tumors may cause frequent, painful, and bloody urination during the night and day. Decaying tissue within the tumor also may be a constant source of infection. Therefore, urinary tract diversion in such individuals may spare them the suffering and sleeplessness of persistent, agonizing urination.
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