Treatment & Management of Bladder Cancer

Cancer Connect

Medically reviewed by Dr. C.H. Weaver M.D. updated 8/2020

Treatments for bladder cancer is tailored to each individual and may include surgery, radiation therapy, chemotherapy, use of precision cancer medicines and and immunotherapy. The specific treatment depends on the stage of the cancer and its genomic profile.

Surgery

Surgery is a common treatment for bladder cancer. The type of surgery depends largely on the stage and the grade of the cancer.

  • Transurethral resection. The doctor may treat early-stage (superficial) bladder cancer with transurethral resection (TUR). During TUR, a cystoscope is inserted into the bladder through the urethra. A small wire loop on the end is used to remove the cancerous area and to burn away any remaining cancer cells with an electric current.
  • Radical cystectomy. For invasive bladder cancer (and when superficial cancer involves a large part of the bladder), the most common type of surgery is radical cystectomy, during which the entire bladder, the nearby lymph nodes, part of the urethra, and the nearby organs that may contain cancer cells—all are removed. In men the prostate, seminal vesicles, and part of the vas deferens are removed. In women the uterus, ovaries, fallopian tubes, and part of the vagina are often removed. If the entire bladder is removed, the patient may undergo another procedure to create a pouch to hold urine. Occasionally, small, localized, muscle-invasive bladder cancers can be removed, sparing the remaining normal bladder in a procedure referred to as partial cystectomy.

Robotic Bladder Cancer Surgery Safe and Effective

Over the past decade, minimally invasive surgical procedures have become an alternative to several types of open surgery. Robotic-assisted radical cystectomy (RARC) is a type of laparoscopic procedure that allows for removal of the cancer without the invasiveness of an open procedure. Robotic surgery is a major surgical procedure performed in a minimally invasive fashion. It involves sophisticated medical devices that allow surgeons to operate through tiny incisions, using enhanced imagery and incredibly precise movements. Robotic-assisted surgery offers improved, magnified visualization in high-definition 3D. Surgeons are able to precisely control the surgical instruments because they offer seven degrees of free motion.

Some studies have demonstrated that when performed by an experienced surgeon robotic-assisted surgery for invasive bladder cancer is effective and results in less bleeding and shorter hospital stays when compared to the traditional open procedure. [1]

Radiation therapy

Radiation therapy uses high-powered energy beams, such as X-rays or protons, to kill cancer cells. Radiation therapy may be used alone or with chemotherapy before surgery to shrink the cancer or after surgery to kill any remaining cancer cells.

  • External radiation. This is usually done at least several days per week on an outpatient basis for several weeks. The high-energy rays are concentrated on the cancerous area from outside the body.
  • Internal radiation. This is done by placing a small container of a radioactive substance into the bladder through the urethra or through an incision in the abdomen and requires a hospital stay. Once the implant is removed, no radioactivity is left in the body.

Intravesicular Therapy

For patients with superficial bladder cancer, intravesical (inside the bladder) chemotherapy or immunotherapy may be used after TUR. A catheter (tube) is placed through the urethra and into the bladder and used to fill the bladder with liquid forms of the drug(s) used. The drugs are left in the bladder for several hours. This treatment is usually done once a week for several weeks and can then be continued once or several times a month for up to a year.

Systemic Therapy

Systemic treatment is any substance that travels through the bloodstream, reaching and affecting cancer cells all over the body. Systemic therapy is used in 3 settings.

  • Adjuvant systemic therapy is used after curative surgery for early stage cancers to reduce the risk of recurrence.
  • Neoadjuvant systemic therapy can be used to “shrink” the cancer prior to surgery to increase the likelihood of successful surgery or liver transplantation.
  • Systemic therapy is used to control symptoms and prolong survival in individuals unable to undergo surgical removal of their cancer.

Traditionally systemic treatment consisted mainly of chemotherapy but increasingly consists of precision cancer medicines and immunotherapy administered alone or in combinations to target specific cancer driving genetic mutations. Systemic treatment is the standard of care for individuals with advanced stage or recurrent cancer.

Precision Cancer Medicine

The purpose of precision cancer medicine is not to categorize or classify cancers solely by site of origin, but to define the genomic alterations in the cancers DNA that are driving that specific cancer. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Precision cancer medicines are one kind of systemic therapy increasingly used instead of chemotherapy as a preferred systemic treatment.

Keytruda (pembrolizumab) is a precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer. It creates its anti-cancer effects by blocking a specific proteins used by cancer cells called PD-1 and PD-L1, to escape an attack by the immune system. Once PD-L1 is blocked, cells of the immune system are able to identify cancer cells as a threat, and initiate an attack to destroy the cancer. There are several PD-1 and PD-L1 inhibitors that work in bladder cancer and they are collectively referred to as “checkpoint inhibitors”. (2-6)

  • Keytruda
  • Imfinzi (durvalumab)
  • Tecentriq (atezolizumab)
  • Bavencio (avelumab)
  • Opdivo (nivolumab)

A clinical study that compared the Keytruda to standard chemotherapy in recurrent bladder cancer that had recurred or progressed following platinum-based chemotherapy demonstrated improved outcomes with the checkpoint inhibitor. (2) Patients who expressed higher levels of the PD-L1 protein have been demonstrated to experience a greater anti-cancer response than those who expressed lower PD-L1 levels. (3,4)

Clinically significant cancer driving genomic alterations have been identified in patients with bladder cancer, several of which can be targeted with available precision medicines. Patients should discuss genomic testing for the following mutations all of which have precision medicines available for treatment or in development.

  • FGFR: the fibroblast growth factor receptor (FGFR) genetic alteration occurs in approximately one in five patients with metastatic urothelial carcinoma. FGFR genes, impact tumor cell proliferation, migration and survival in both non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer. (6,7,8)
  • KRAS
  • BRAF
  • MSI-High
  • NTRK
  • EGFR

Immunotherapy

Immunotherapy uses the body’s natural ability (immune system) to fight cancer and is used for the treatment of superficial bladder cancer following TUR and for the treatment of more advanced cancers. For superficial bladder cancer immunotherapy can be used within a few weeks of TUR surgical removal of the cancer.

  • Bacillus Calmette-Guerin (BCG). This is the most common form of immunotherapy. BCG solution contains live, weakened bacteria related to cow tuberculosis that stimulate the immune system to kill cancer cells in the bladder. The bladder is filled with the solution through a catheter and left for about two hours. Patients generally undergo this treatment once a week for about six weeks.
  • Interferon. This is another form of biologic therapy, which involves the administration of large amounts of a synthetic protein normally made by the body to activate and energize the immune system. Recent studies suggest that a combination of BCG plus interferon may be particularly active against aggressive or refractory superficial bladder cancer, especially CIS.

Treatment of Bladder Cancer by Stage

Stage 0 (T0): Patients with stage 0 bladder cancer have the earliest stage of cancer that involves only the innermost layers of cells in the bladder. Depending upon the appearance of the cells under the microscope, stage 0 transitional bladder cancer is pathologically classified as either noninvasive papillary carcinoma or carcinoma in situ (CIS), both of which are considered to be “superficial” bladder cancers.

Stage I (T1): Patients with stage I bladder cancer have cancer that invades beneath the surface of the bladder into connective tissue, but does not invade the muscle of the bladder and has not spread to lymph nodes. This is also classified as a “superficial bladder cancer.”

Stage II (T2): Patients with stage II bladder cancer have cancer that invades through the connective tissue into the muscle wall, but has not spread outside the bladder wall or to local lymph nodes. Patients with cancer invading the inner half of the muscle of the bladder wall have a better outcome than patients with invasion into the deep muscle (outer half of the muscle of the bladder wall). Stage II bladder cancer is classified as a “deep” or “invasive” bladder cancer.

Stage III (T3): Patients with stage III bladder cancer have cancer that invades through the connective tissue and muscle and into the immediate tissue outside the bladder and/or invades the prostate gland in males or the uterus and/or vagina in females. With stage III bladder cancer, there is no spread to lymph nodes or distant sites. Stage III bladder cancer is also classified as a “deep” or “invasive” bladder cancer.

Stage IV (T4): Patients with stage IV bladder cancer have cancer that has extended through the bladder wall and invaded the pelvic and/or abdominal wall and/or has lymph node involvement and/or spread to distant sites. Stage IV bladder cancer is also referred to as “metastatic” bladder cancer. Recurrent Bladder Cancer: Patients with recurrent bladder cancer have cancer that has returned following initial treatment with surgery, radiation, chemotherapy or immunotherapy.

Recurrent: Patients with recurrent bladder cancer have cancer that has returned following initial treatment with surgery, radiation, chemotherapy or immunotherapy.

Surgery for Bladder Cancer

The optimal treatment of bladder cancer may require involvement of several different physicians, including a urologist, medical oncologist and/or radiation oncologist. Medical oncologists are specialists in the management of cancer and use of anti-cancer treatments such as chemotherapy. Radiation oncologists are specialists in the use of radiation to treat cancer and urologists are surgeons and experts in the management of cancers involving the urinary system. There are several different surgical procedures that are performed by urologists for the diagnosis and treatment of the different stages of bladder cancer.

Transurethral Resection (TUR)

A transurethral resection (TUR) is an operation that is performed for both the diagnosis and management of bladder cancer. During a TUR, a urologist inserts a thin, lighted tube called a cystoscope into the bladder through the urethra to examine the lining of the bladder. The urologist can remove samples of tissue through this tube or can remove some or all of the cancer in the bladder. The urologist can also use electrical (cautery or fulguration) or laser thermal destruction of stage 0-I superficial bladder cancers. A TUR causes few problems, although patients may have some blood in their urine and difficulty or pain when urinating for a few days afterward.

TUR is used to treat patients with superficial bladder cancers (non-invasive papillary carcinoma and carcinoma in situ). Repeated TURs are frequently performed throughout the life of patients with superficial bladder cancers. At the time of TUR, chemotherapy agents and biological agents, such as BCG, are often instilled into the bladder. Surgeons can also cauterize (electrical heat) or apply a laser for heat to kill visualized superficial cancers during a TUR.

TUR can also be utilized to remove all or a part of stage II-III bladder cancer in patients scheduled to receive chemotherapy and radiation therapy for bladder-sparing therapy approaches.

Robotic Bladder Cancer Surgery Safe and Effective

Minimally invasive surgical procedures have become an alternative to several types of open surgery. Robotic-assisted radical cystectomy (RARC) is a type of laparoscopic procedure that allows for removal of the cancer without the invasiveness of an open procedure. Robotic surgery is a major surgical procedure performed in a minimally invasive fashion. It involves sophisticated medical devices that allow surgeons to operate through tiny incisions, using enhanced imagery and incredibly precise movements. Robotic-assisted surgery offers improved, magnified visualization in high-definition 3D. Surgeons are able to precisely control the surgical instruments because they offer seven degrees of free motion.

Some studies have demonstrated that when performed by an experienced surgeon robotic-assisted surgery for invasive bladder cancer is effective and results in less bleeding and shorter hospital stays when compared to the traditional open procedure.[1] Although these retrospective clinical studies have suggested that RARC leads to fewer complications and a shorter hospital stay compared with open surgery, supporting data from randomized comparative trials has been lacking.

Investigators at Sloan Kettering have now reported that RARC may offer no advantages to a traditional open cystectomy. They performed a clinical trial that directly compared open and RARC in patients with newly diagnosed invasive bladder cancer. All surgeries were performed by the same seven surgeons, each of whom had at least 10 years of experience. The 90-day complication rate was 62% with robotic surgery and 66% with open surgical resection of the bladder. The robotic procedure failed to shorten hospital stays, with a mean duration of 8 days in both groups. Severe complications also occurred in a similar proportion of patients in the two groups. Robot-assisted laparoscopic cystectomy was associated with less intraoperative blood loss but required significantly more time to complete, averaging 456 minutes versus 329 minutes with open cystectomy.[2]

Radical Cystectomy (Complete Surgical Removal of the Bladder)

A radical cystectomy consists of the surgical removal of the bladder as well as the tissue and some of the organs around it. For men, the prostate and the seminal vesicles, and possibly the urethra, are often removed. For women, the uterus, ovaries, fallopian tubes, part of the vagina, and the urethra are often removed. A pelvic lymph node dissection, removal of the lymph nodes in the pelvis, may also be performed to determine whether the cancer has spread to these lymph nodes. Pelvic lymph node dissection adds little to the overall side effects of radical cystectomy, improves staging accuracy and may be curative in some patients with minimal lymph node involvement.

Because the bladder is removed, doctors must design an alternate way for the body to store and pass urine. This is often referred to as a urinary diversion technique and is described in complete detail below in the section entitled “Creation of Alternative Bladders and Neobladders.” Radical cystectomy with preservation of sexual function can be performed in some men and new forms of urinary diversion can eliminate the need for an external urinary appliance.

Segmental or Partial Cystectomy

A segmental or partial cystectomy is an operation during which a portion of the bladder is removed and the ends are sewn back together. It is sometimes performed for treatment of patients with multiple superficial cancers or large superficial cancers in an attempt to avoid removing the entire bladder. However, there are very few situations where this is done.

The application of segmental or partial cystectomy to the treatment of invasive bladder cancer remains controversial. In selected cases with small cancers, the results may be similar to those observed after radical cystectomy. However, the potential for development of cancer in the remaining bladder is still present.

After segmental cystectomy, patients may not be able to hold as much urine in their bladder. In most cases, this problem is temporary; however, some patients may have long-lasting changes in bladder capacity.

Creation of Alternative Bladders or Neobladders

Because surgical treatment of bladder cancer removes the bladder, doctors must design an alternate way for the body to store and pass urine. This is often referred to as a urinary diversion technique. Sometimes, this involves using part of the intestine to construct a tube that carries urine from the ureters to an opening (called a stoma) to the outside of the body. The procedure to construct this stoma is called an ostomy or urostomy. Many researchers have also been studying more permanent ways to allow urine to be stored and passed to help improve urinary function and quality of life. This often involves creating a substitute bladder, sometimes called a neobladder.

The construction of a neobladder involves the use of a segment of the intestine between the ileum (last part of the small intestine) or colon (part of the large intestine) to form a new bladder, referred to as an ileocolonic neobladder. The ureters, which deliver urine from the kidneys to the bladder, are attached to one end of the neobladder. Urine collects in the storage pouch and empties into a stoma (opening in the abdominal wall) through the abdomen to a collection bag. Whenever possible, the neobladder is connected to the urethra and voiding can be more natural.

The use of an intestinal neobladder is an extremely effective form of continent diversion. Complete day and night continence can be achieved in approximately 80% patients. Mild to moderate stress incontinence occurs in 10% of patients and severe stress incontinence in 5%. Patients older than 70 years are more likely to have trouble with continence than younger patients. However, in one retrospective analysis from a single institution, elderly patients (70 years of age or older) in good general health were found to have similar clinical and functional results following radical cystectomy as younger patients. This is an important observation because it suggests that medical condition is more important than age for outcome of surgery.

Radiation Therapy for Bladder Cancer

Radiation therapy may be an integral part of the treatment of bladder cancer. However, since cancer of the bladder is not exclusively treated with radiation therapy, it may be important for patients to be treated at a medical center that can offer multi-modality treatment involving medical oncologists, radiation oncologists, and surgeons.

Radiation therapy or radiotherapy uses high-energy rays to damage or kill cancer cells by preventing them from growing and dividing. Similar to surgery, radiation therapy is a local treatment used to eliminate or eradicate cancer that can be encompassed within a radiation field. Radiation therapy is not typically useful in eradicating cancer cells that have already spread to other parts of the body. Radiation therapy may be externally or internally delivered. External radiation delivers high-energy rays directly to the cancer from a machine outside the body. Internal radiation, or brachytherapy, involves the implantation of a small amount of radioactive material in or near the cancer. Currently the use of radiation therapy alone as a primary treatment for bladder cancer has largely been replaced by the combined use of radiation therapy and chemotherapy. The main use of radiation therapy is in combination with chemotherapy for treatment of patients with stage II-III disease or recurrent cancer. However, radical cystectomy remains the primary modality for the treatment of stages II and III bladder cancer.

Chemotherapy and Radiation Therapy for Primary Treatment

Over the past decade, many clinical trials in the United States and Europe have evaluated the combination of radiation and chemotherapy as initial treatment of patients with stage II-III bladder cancer for the purpose of preserving the bladder. Bladder-preserving therapy is appealing because patients who achieved a complete response to treatment can often avoid surgical removal of the cancer unless they experience recurrence of their cancer. In addition to helping patients avoid cystectomy, early treatment with chemotherapy may also kill cancer cells that have already spread away from the bladder.

In some clinical trials, approximately half or more of patients who were treated with bladder-preserving therapy (initial TUR of as much cancer as possible, plus chemotherapy and radiation therapy) survived cancer-free three to four years after treatment. Although these results appear as good as those observed with surgery (radical cystectomy), there have been no direct comparisons of radical cystectomy to combination chemotherapy and radiation therapy. While bladder-preserving therapy has been widely adopted for the treatment of stage II-III bladder cancer, some physicians still think it should be limited to clinical trials and not adopted as standard therapy.

Palliative Radiation Therapy

The goal of palliative therapy is to decrease the symptoms of cancer, such as pain, in order to improve a patient’s quality of life. For some patients with advanced bladder cancer, radiation therapy may be used to shrink the cancer and relieve cancer symptoms.

Delivery of Radiation Therapy for Bladder Cancer

Modern radiation therapy for bladder cancer is administered via machines called linear accelerators, which produce high energy external radiation beams that penetrate the tissues and deliver the radiation dose deep into the areas where the cancer resides. These modern machines and other state-of-the-art techniques have enabled radiation oncologists to significantly reduce side effects, while improving the ability to deliver a curative radiation dose to cancer-containing areas and minimizing the radiation dose to normal tissue. For example, with modern radiation therapy, skin burns almost never occur, unless the skin is being deliberately targeted or because of unusual patient anatomy or extension of the cancer close to the source.

Simulation

After an initial consultation with a radiation oncologist, the next session is usually a planning session, which is called a simulation.During this session, the radiation treatment fields and most of the treatment planning are determined. Of all the visits to the radiation oncology facility, the simulation session may actually take the most time. During simulation, patients lay on a table somewhat similar to that used for a CT scan. The table can be raised and lowered and rotated around a central axis. The “simulator”machine is a machine whose dimensions and movements closely match that of an actual linear accelerator. Rather than delivering radiation treatment, the simulator lets the radiation oncologist and technologists see the area to be treated. The room is periodically darkened while the treatment fields are being set and temporary marks may be made on the patient’s skin with markers. The radiation oncologist is aided by one or more radiation technologists and often a dosimetrist, who performs calculations necessary in the treatment planning. The simulation may last anywhere from 15 minutes to an hour or more, depending on the complexity of what is being planned.

Once the aspects of the treatment fields are satisfactorily set, x-rays representing the treatment fields are taken. In most centers, the patient is given multiple tattoos which mark the treatment fields and replace the marks previously made with markers. These tattoos are not elaborate and consist of no more than pinpricks followed by ink, appearing like a small freckle. Tattoos enable the radiation technologists to set up the treatment fields each day with precision, while allowing the patient to wash and bathe without worrying about obscuring the treatment fields. Radiation treatment is usually given in another room separate from the simulation room. The treatment plans and treatment fields resulting from the simulation session are transferred over to the treatment room, which contains a linear accelerator focused on a patient table similar to the one in the simulation room. The treatment plan is verified and treatment started only after the radiation oncologist and technologists have rechecked the treatment field and calculations and are thoroughly satisfied with the setup.

Side Effects of Radiation Therapy

The majority of patients are able to complete radiation therapy for bladder cancer without significant difficulty. Side effects and potential complications of radiation therapy are limited to the areas that are receiving treatment with radiation. The chance of a patient experiencing side effects, however, is highly variable. A dose that causes side effects in one patient may cause no side effects in other patients. If side effects occur, the patient should inform the technologists and radiation oncologist because treatment for these side effects is almost always available and effective.

Radiation therapy to the abdominal/pelvic area may cause diarrhea, abdominal cramping, or increased frequency of bowel movements or urination.These symptoms are usually temporary and resolve once the radiation is completed. Occasionally abdominal cramping may be accompanied by nausea.

Blood counts can be affected by radiation therapy. In particular, the white blood cell and platelet counts may be decreased. This is dependent on how much bone marrow is in the treatment field and whether the patient has previously received or is receiving chemotherapy. These changes in cell counts are usually insignificant and resolve once the radiation is completed. However, many radiation therapy institutions make it a policy to check the blood counts at least once during the radiation treatments.

It is not unusual for some patients to note changes in sleep or rest patterns during the time they are receiving radiation therapy and some patients will describe a sense of tiredness and fatigue.

Late complications are infrequent following radiation treatment of bladder cancer. Potential complications do include bowel obstruction, ulcers or cancers caused by the radiation. The probabilities of these late complications are also affected by previous extensive abdominal or pelvic surgery, radiation therapy and/or concurrent chemotherapy.

References

  1. Parekh DJ, Messer J, Fitzgerald J, et al. Perioperative outcomes and oncologic efficacy from a pilot prospective randomized clinical trial of open versus robotic assisted radical cystectomy. Journal of Urology. 2013; 189(2): 474-479.
  2. Merck’s KEYNOTE-045 Studying KEYTRUDA® (pembrolizumab) in Advanced Bladder Cancer (Urothelial Cancer) Meets Primary Endpoint and Stops Early
  3. United States Food and Drug Administration. (2016.) News Release. FDA approves new, targeted treatment for bladder cancer.
  4. Durvalumab (Imfinzi)
  5. FDA approves new, targeted treatment for bladder cancer. Accessed May 31, 2016.
  6. Helsten T, Elkin S, Arthur E, et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2015;22(1):259-267.
  7. Tomlinson DC, Balbo O, Harnden P, et al. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol. 2007;213(1):91-98.
  8. Casadei C, Dizman N, Schepisi G, et al. Targeted therapies for advanced bladder cancer: new strategies with FGFR inhibitors. Ther Adv Med Oncol. 2019;11:1-8.
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