Bladder Cancer Standard of Care: A Patient Translation of International Guidelines

At a BCAN meeting a bladder cancer survivor asked: "why isn't a patient tranlation of the guidelines for bladder cancer care available so patients can know if the care they receive is appropriate?"  To accommodate this excellent request, I summarized the international guidelines and asked my wife Wanda, a nurse who previously ran a branch of the NCI phone service "1 800 4 CANCER" translate it into lay language.  We hope this helps!

Recent study finds that a very small percent of patients with bladder cancer receive optimal care as recommended by national and international guidelines.  We hope to help patients make informed decisions on their care by providing an understandable translation of a recent summary of international guidelines. General guidelines cannot apply to every individual’s circumstance, so the care for you may differ from the guideline.  Your doctor can best explain how the guidelines apply to your treatment.

Bladder cancer is divided into the broad groups of non-muscle invasive (about 80% of tumors) and muscle-invasive bladder cancer, tumors that have grown into the thick muscular wall of the bladder.  Non-muscle invasive tumors can generally be treated with day surgery and medicine placed within the bladder.  Tumors that have grown into the muscle of the bladder generally require much more aggressive treatment such as bladder removal, chemotherapy and/or radiation therapy.

Non-Muscle Invasive Bladder Cancer

Risk Groups

Treatment of bladder cancer that has not grown into the muscular bladder wall varies according to the risk that the tumor will come back and grow more deeply into the bladder or spread (metastasize).  The most important factors in determining a patient’s risk group are cancer grade (the degree of microscopic abnormality of the cancer cells) and the cancer stage (location of the tumor in the bladder wall). 

Tumor Grade: Grade is divided into two groups.  Low grade tumors have cells that have a nearly normal microscopic appearance, while high grade tumors have cells that are irregular and variable in size and shape and are clearly different in appearance from normal cells. 

            Tumor Stage: The bladder has 4 layers:  1) the urothelium  (the thin inner lining); 2) the lamina propria (a layer of vessels, supportive tissue  and small muscle bands); 3) the muscularis propria  (a thick muscle layer that contracts to empty the bladder); and 4) the surrounding layer of fat.  These layers determine the primary or tumor stage of bladder cancer.  Tumors that have no invasion and are limited to the inner cell lining (urothelium) are stage Ta; those invading the immediate underlying supportive tissue (lamina propria) are stage T1.  Carcinoma in situ (CIS or cancer “in place”) is a special stage and category of bladder cancer.  CIS is high grade cancer that has neither invaded nor formed a mass (tumor) within the bladder.  It grows on the surface of the bladder, replacing normal cells, and has a very high risk of becoming invasive.  CIS is always placed in the high risk category.  All three stages above, CIS, Ta and T1 are non-muscle invasive tumors. 

Muscle Invasive and Metastatic Bladder Cancer Staging

Tumors that invade the true muscular wall (muscularis propria or detrusor muscle) are stage T2, and those that go through the muscle to the fat around the bladder are stage T3.  Tumors that extend beyond the prostate to other organs or structures are stage T4.  Additional subdivisions of tumor stage are of less importance, and are shown in the table below.  Tumor that has spread to lymph nodes is stage N+ (N1 is a single node positive, N2 is a node with 2cm of tumor or more than one node positive, and N3 is more than 5cm of node involvement).  Distant spread of tumor to lung, liver or bone, for example, is stage M+ or “M1”.  The current staging system is listed in the table below.

Staging System of Bladder Cancer

T: Primary Tumor

                        TX       Primary tumor cannot be assessed

                        T0        No evidence of primary tumor

                        Ta        Non-invasive papillary carcinoma

                        Tis       Carcinoma in situ: “in place”

                        T1        Tumor invades lamina propria or subepithelial connective tissue

                        Non muscle-invasive tumors above, muscle invasive below this line

                        T2        Tumor invades muscle

                                    T2a      Tumor invades superficial muscle (inner half)

                                    T2b      Tumor invades deep muscle (outer half)

                        T3        Tumor invades fat around the bladder :

                                    T3a      Microscopically (seen only with the microscope)

                                    T3b      Macroscopically (seen with the naked eye)

T4        Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall

                        T4a      Tumor invades prostate, uterus or vagina

                        T4b      Tumor invades pelvic wall or abdominal wall

N-Lymph nodes

            NX      Regional (in the pelvis) lymph nodes cannot be assessed

            N0       No regional lymph node metastasis

N1       Metastasis in a single lymph node 2 cm or less in greatest dimension

N2       Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension

N3       Metastasis in a lymph node more than 5 cm in greatest dimension

M: Distant metastasis

                        MX      Distant metastasis cannot be assessed

                        M0       No distant metastasis

                        M1       Distant metastasis

Definitions of Treatment Guideline Terminology

Standard of Care: Treatment results are sufficiently known (e.g. as based on randomized clinical trials) to provide near unanimous agreement on management.

Recommendation: Treatment results are sufficiently known to provide meaningful recommendations supported by a majority of health providers.

Option: Results are not sufficiently known to provide a meaningful recommendation or superiority of treatments is not established.

Treatment of non-muscle invasive bladder cancer

Low Risk Bladder Tumor:

Low risk tumors are small or solitary low grade (including  PUNLMP, see glossary) tumors that have no invasion (Ta).  Low grade, Ta tumors are treated with transurethral resection (TURBT, surgical removal through the urethra).  Ideally, muscle is included in the biopsy specimen to be certain that it is free of tumor.  Deep biopsy does carry some risk of bladder perforation, and your urologist may elect to avoid that risk.  It is recommended (standard of care) that a single instillation of chemotherapy be given soon (preferably within 6 hours) after surgery to reduce the risk of recurrence from seeding.  BCG is never given immediately post operatively and is not recommended for low risk tumors.  No further treatment is required.  The risk of recurrence is medium, so follow up cystoscopy is required, even though the risk of disease progression is low.

Intermediate Risk Bladder Tumor:

Intermediate risk tumors are low grade tumors that are multiple, large, or recurrent but still stage Ta (non-invasive).  Initial treatment is complete removal of tumors followed by immediate administration of chemotherapy in the bladder (intravesical chemotherapy) to prevent seeding.  It had been previously recommended that intermediate risk patients be treated with a further course of intravesical chemotherapy, and this may be best for patients at the lower spectrum of intermediate risk disease, but new data from a clinical trial in Europe that included 497 patients with intermediate risk disease showed that the 3 week maintenance BCG schedule, when compared with the same schedule of intravesical chemotherapy with Epirubicin, reduced metastasis by 58% and bladder cancer death by 65%.  In other words, patients treated with 3 week maintenance BCG had one third the risk of dying of bladder cancer compared with those treated with chemotherapy.  BCG is therefore now recommended for most patients with intermediate risk disease.

High Risk Bladder Tumor:

High risk tumors are high grade tumors and/ or those with invasion (T1), or associated CIS.  Pure CIS, without a visible tumor, is also high risk.  BCG is the treatment of choice for high risk disease.  It is especially important to accurately stage high risk patients by including muscle in the specimen, widely and deeply removing the tumor.  If muscle is not in the specimen repeat resection (TURBT) is recommended, and even with muscle in the specimen repeat resection is recommended by some guidelines (European) to reduce the risk of recurrence.  Immediate postoperative chemotherapy is recommended by some guidelines to reduce seeding.  For the highest of high risk patients, those with multiple or large high grade, T1 tumors and CIS, immediate cystectomy is an optional initial treatment.

Summary of Treatment Guidelines for Non Muscle-Invasive Disease:

TURBT (tumor resection): Complete removal of tumor (standard of care) with biopsy of muscle at the base of and the margins (edges) of larger tumors (recommendation).  Biopsy of the prostatic urethra is recommended for patients with CIS, multifocal (multiple) tumors and when visible abnormalities of the prostatic urethra is present.  Biopsy of normal appearing bladder (random bladder biopsy) is recommended when cytology is positive, and abnormal appearing areas of the bladder should be biopsied.

Immediate Post Operative Chemotherapy: Recommended for all patients undergoing TURBT for non- muscle invasive bladder cancer.  Choice of chemotherapy (Mitomycin C, Epirubicin, Thiotepa, doxorubicin etc.) is optional.

Adjuvant Intravesical Chemotherapy: Additional chemotherapy (or BCG immunotherapy) is recommended for patients with intermediate risk disease.  Chemotherapy should not be continued beyond 12 months.

BCG Immunotherapy: BCG is recommended for intermediate risk and standard of care for high risk bladder cancer.  Maintenance BCG is recommended for at least a year.  Three week maintenance therapy given for 3 years, but not other schedules, has been confirmed to reduce recurrence and progression compared with 6 week induction and compared with chemotherapy also reduces metastasis and cancer death.

Treatment of Muscle Invasive Bladder Cancer

The recommended treatment for tumors that have invaded the muscular wall of the bladder is radical cystectomy (below) with preoperative systemic chemotherapy.  Chemotherapy plus radiation therapy is an option, and is recommended for patients who are not medically fit for major surgery.  Patients with disease that has spread to other parts of the body require systemic chemotherapy.  Cystectomy or radiation therapy is sometimes used to treat local symptoms.

Radical Cystectomy: Surgical removal of the bladder with, in men, the prostate and in women often the underlying portion of the vagina as well as the uterus, is recommended for patients with bladder cancer that has grown into the muscular wall of the bladder (Stage T2 or higher).  Select patients with very high risk of progression with T1 disease plus CIS, and those who fail BCG immunotherapy and have recurrent high risk disease are also candidates for cystectomy.  Current recommendation is to give systemic (intravenous) combination chemotherapy before surgery and perform a thorough and wide removal of lymph nodes in the pelvis.  An option for patients who are not medically fit for surgery or decline bladder removal is chemotherapy plus radiation therapy.

Urinary Diversion: After cystectomy primary options for drainage of urine include an ileal loop or Bricker diversion, where a segment of the small intestine is brought to the skin on the lower abdominal wall to drain urine into a bag; an orthotopic neobladder or Studer bladder, where a “new bladder” is constructed from the small bowel and sewn to the urethra; and an Indiana Pouch or continent cecal  bladder, an internal bladder made of the large bowel, brought to the belly button (umbilicus) and drained by intermittent catheterization.

Glossary

Adjuvant chemotherapy:  An adjuvant treatment is a supplemental or additional therapy, and adjuvant chemotherapy is additional medication that kills or decreases growth of cancer.

BCG: Bacillus Calmette-Guerin is a live attenuated (weakened) vaccine for tuberculosis that stimulates the immune system, primarily the white blood cells or lymphocytes.  These cells and others then attack and destroy bladder cancer cells. 

Combination chemotherapy: Two or more chemotherapeutic drugs can work together to kill cancer cells.  In bladder cancer, common combinations are cisplatin and gemcitabine (with or without paclitaxel) and Methotrexate, Vinblastine, Adriamycin and Cisplatin (MVAC). 

CIS: Carcinoma in situ.  Unlike tumors elsewhere in the bladder, where CIS or “cancer in place” is early malignancy that is readily treated and has a good prognosis, CIS of the bladder is an aggressive form of bladder cancer.  Before the advent of BCG, the majority of patients with CIS would develop muscle invasive disease within 5 years.  With BCG about 80% of patients will have complete response and most of those on 3 week maintenance will remain disease free for 5 or more years.

Grade: Tumor grade is the microscopic appearance of the cancer.  In bladder cancer grade is divided into two groups, low and high grade.  Low grade tumors have a cellular appearance that is similar to normal cells.  High grade tumors have an abnormal, irregular appearance and are more likely to recur and progress.

Intravenous: Given within the venous system.

Intravesical: Given within the bladder.

Invasive: Growing into.

Metastasis: Spread of malignancy to distant sites.

Neoadjuvant: “New adjuvant,” referring to the practice of giving chemotherapy before surgery.

Progression: Increase in tumor stage, often specifically referring to stage T2 or greater.

PUNLMP: Papillary Urothelial Neoplasia of Low Malignant Potential, a very low grade polyp in the bladder that has a good prognosis and may not even be malignant.

Recurrence: Bladder tumor that comes back after removal.  This can be tumor that was not completely resected, that implanted or seeded at the time of surgery, or an entirely new tumor.

Risk Group: Treatment of non-muscle invasive bladder cancer varies according to the risk for tumor recurrence and progression.  Surgery is important for all groups, chemotherapy given in the bladder is preferred for lower risk groups and BCG immunotherapy for higher risk groups.

Resection: Surgical removal of bladder tumor, generally through the urethra (transurethral).

Stage: The location of bladder tumor, as described in detail above.

Seeding: Implantation and growth of tumor cells.  This can occur within the bladder during transurethral resection or in the pelvis during open bladder surgery such as partial or radical cystectomy.

TURBT: transurethral resection of bladder tumor (see resection above).