BCG Related Infections

Dear Dr. Lamm,

I am an 78 year old retired general surgeon in Dallas, Texas, with transitional cell carcinoma in situ of my urinary bladder and, now, probable BCG-related right epididymo orchitis.  I have undergone induction BCG treatment as per your protocol, followed by maintenance Rx. consisting of one bladder irrigation with BCG once monthly.  My care has been under the direction of a board certified urologist (Michael Gross, M.D.) a member of Dr. Mel Kadesky's urology group.   I am now NED according to repeat cystograms and biopsies at three-month intervals that have shown no residual malignancy in either of the last two exams.  FISH tests to date have been non diagnostic because of insufficient cells to examine.  Altogether, I have been NED eight months after one induction course of BCG followed by maintenance as described above.  For the past six months the irrigations have been associated with significant pain and swelling of my right testicle.  I have had no symptoms of BCG systemic sepsis.  Recently, I developed a right scrotal fistula.  It is, perhaps, significant that 20 years ago I had a TUIP to release a bladder neck stricture and excision of multiple bladder diverticulae.  Several years later, I underwent a left epididymectomy to remove a large spermatocele.  There is, therefore, no epididymus on the left but there is one on the right where the abscess and fistula are located.

I have recently been placed on treatment for the tubercular left epidymo-orchitis with Isoniazid 300 mgm, Rifampin 600 mgm, and Ethambutal 1200 mgm daily.  A year of treatment is planned.  Abscess cultures are pending.  I am totally asymptomatic except for a mass in my left scrotum and a small amount of clear liquid drainage from the fistula.  

My urologist has never seen this type of complication from BCG therapy.  Apparently there is no one in Dallas who has any experience with this complication.  That is why I am turning to you for advice.  

To begin with, my urologist tells me I must forego any further BCG therapy.  I am most reluctant to do this.  If the epididymus became infected could the previous TUIP have set the stage for this complication by allowing retrograde flow of the irrigation fluid into the prostate and thence to the epididymis?  If so, could this source of infection be eliminated by a right epididymectomy and orchiectomy and allow for resumption of BCG?  As noted I have previously undergone a left epididymectomy.

Finally, do you have any suggestions about how to improve the results of the FISH tests?  At this point I face loss of maintenance treatment with BCG irrigations as well as absence of diagnostic quality FISH tests to monitor for recurrent disease.  I would be most grateful for your suggestions.

Very truly yours,

John H. Cottey, M.D.

Dear Dr. Cottey,


You are absolutely correct. The problem can be solved, I believe, with a right epedidymectomy (on your antibiotics).  This will speed your recovery, reduce the amount of time you need to be on TB antibiotics, and allow you to continue on BCG as needed.  This is a recognized complication of BCG therapy, and yes, it is related to reflux down the vas.  The "good" news is that not only are you cancer free, but the infection will reduce the amount of BCG maintenance you need in the future.  When you do return to BCG maintenance, I strongly suggest reduced dose. 
FISH and cytology can be improved by doing a bladder wash at the time of cystoscopy.  We start with a small (20cc) volume of saline and use all the residual urine in the specimen.  We also wash the prostatic urethra, which is at risk for developing CIS in the ducts.
Best regards,
Don Lamm, MD

Techniques to Improve Bladder Function

Techniques to Improve Bladder Function without Drugs

Don Lamm, MD, BCG Oncology

The bladder has two primary jobs, holding and discharging urine.  Drugs can be used to relax the bladder and improve the “holding” function, or relax the outlet of the bladder to improve voiding.  There are also ways to train the bladder to function better, with or without the help of drugs.  One helpful technique is to make a voiding diary to see and even measure response to treatment.

Incomplete emptying: If the bladder does not completely empty there is an increased risk of infection, and there is less functional capacity of the bladder because there is less room for additional urine.  This results in frequent voiding and further fatigue of the bladder.  The bladder is a muscle, and emptying is work.  It can tire during the process and stop before the bladder is empty.  By waiting a few minutes after voiding, and sometimes by actually pushing down on the top of the bladder with your hand, the bladder can empty the remaining urine.  Double voiding like this can reduce the risk of infection and decrease the number of trips to the bathroom.

Frequent and Urgent Voiding: There are no “volume receptors” in the bladder, only “pressure receptors.”  The urge to urinate occurs whenever the bladder contracts, regardless of the volume of urine.  Contraction may be stimulated by irritation of the bladder from surgery, infection, radiation, foreign body such as a catheter or ureteral stent, or by reflex stimulation of nerves.  Medications such as prescription bladder relaxants or over the counter medicines like Alka Seltzer or sodium bicarbonate (for acid urine) or ibuprophen (for inflammation) may help, but you can also “train” your bladder and reduce or eliminate the need for medication.  The bladder can reflexly contract every time you hear water running or see porcelain.  If you void each time the bladder contracts, the volume at which the bladder contracts may continue to decrease, shrinking the effective capacity of the bladder.  You can suppress the urge (bladder contraction) by extending the interval between voiding.  This, of course, must be done gradually and carries a risk of urine leakage.  One technique used to suppress the urge to urinate is to give 5 quick Kegel’s contractions and two long, slow, maximal contractions of the sphincter when you have the urge.  (See our handout on Kegel’s exercise for more specifics).  The urge should pass, but will return later.  It is best to try to urinate when you do not have the severe urge if you can.  In short, try to stretch the bladder by holding your urine 2 or more times a week to improve the storage function of the bladder, and train your bladder to not contract by suppressing the urge to urinate reflexly when you pass a bathroom with “5+2” contractions and voiding, when possible, between urges. 

Is there anything additional I can do?

Hello Dr. Lamm,

I trust you are doing well. I have a couple of questions that I'm hoping you can help me with. I was originally diagnosed with T1 with CIS (12/2010) after having a 3 cm papillary tumor resected in 11/2010. I have since had the 6 week BCG induction series and 3, three week maintenance instillations of BCG the last of which was completed on 3/15/2012. I have been cancer free thus far with no recurrences since 3/2011. My next Blue Light Cysto is scheduled for 6/21/2012. To date, the only tests I have had at my quarterly Cystos are Cytology, one PSA & a biopsy at my last Cysto. Would you recommend anything additional at this juncture? i.e. Upper & lower ureter check, Prostate & Prostate Ureter check, C/T Pylogram, retrogrades, washes, kidney check, etc. 

As you imply, it is important to also follow the upper tracts and prostate in CIS and high grade disease.  I once recommended annual upper tract evaluations, but if the bladder remains clear and cytologies and fish are negative, I think this is too much (even potentially carcinogenic). 

A CT

urogram or retrograde at 1-3 years would be good.  I like to do a fish when extending the intervals between cystoscopy (or at any time I am worried about recurrence).  At cysto I routinely wash the prostatic urethra, but a F/U biopsy of the prostate is also good.  This, plus retrogrades and ureteral washes makes for a good certainty that there is no occult disease.  Again, every 1-3 years is in the ballpark.

My second question relates to the strength of my BCG maintenance dosages. To date, I have been getting full strength but I have read that reduced dosages-i.e. 33%-might be advisable and even more effective so as to not hinder the immune response and/or in order to prolong the ability to tolerate the

BCG.  Full strength is fine if you are tolerating it, but most patients have increasing symptoms that need to be moderated by reduced dose. 

Best, DL

Diet and Lifestyle Considerations for Bladder Cancer Patients

Diet and Lifestyle Considerations for Bladder Cancer Patients

Nutrition plays an important role in the development of cancer.  Dietary factors such as increased fat and animal protein, especially when broiled, can promote development of cancer, but many foods such as soy, garlic, cruciferous vegetables, fruits, tea, and even some chocolates have beneficial ingredients such as antioxidants that may reduce the risk of cancer.  With a healthy diet and life style, which includes regular exercise and avoidance of carcinogens including tobacco, supplemental vitamins may not be needed.  Many of us, however, may benefit from supplemental vitamins.  Oncovite, two tablets twice a day, is now recommended for bladder tumor patients.  Diet and lifestyle can also play a significant role.  Here are some suggestions:

I recommend increasing fruit and vegetable consumption to a minimum of 6 servings a day.  The vegetarian diet is optimal for reduction of carcinogens.   Some fruits and vegetables may contain more phytochemicals that protect against cancer than others.  Beneficial effects have been reported for tea, soy, cruciferous vegetables (broccoli, cauliflower, brussel sprouts), citrus, berries, tomatoes and other red/orange vegetables, and garlic.  Studies show that carcinogenic DNA adducts in the urine (chemicals that combine with genes to promote cancer) are significantly reduced with high intake of fruit and vegetables.  Epidemiologic studies suggest that fruit may be especially beneficial in the prevention of bladder cancer.  It is true that cranberry juice can protect against bladder infection, one of the causes of bladder cancer.  Cranberries and other small dark berries are very high in antioxidants.  Pomegranate juice appears to be very promising in studies of prostate and other cancers, and may have a role in bladder cancer.  There is some suggestion that green tea, soy and garlic may reduce the risk of bladder cancer.  Many are unable to change their diet and get enough of the beneficial chemicals (phytochemicals) in plants.  A list of health food supplements is available to help guide your nutritional therapy.

Additional life style/dietary changes may be beneficial in the prevention of bladder cancer:

It is important to avoid any carcinogen exposure.  While epidemiologic studies have not confirmed the carcinogenicity of artificial sweeteners, I would recommend avoiding excess use.  Anecdotally, some patients with a history intractable tumor recurrence report remaining tumor free after discontinuing soft drinks.  Second hand smoke, pesticides, diesel fuel and organic chemical exposure, as well as excessive exposure to dyes should also be avoided.

Increased intake of water that is free of arsenic, pesticides and other bladder carcinogens appears to be helpful.  Studies by Dr. Michaud and others show that increased fluid intake reduces the risk of bladder cancer, but we have not demonstrated an effect yet in reducing recurrence. 

We have demonstrated in an animal model that garlic can actually reduce the growth of bladder cancer and even prolong survival.  If interested in such alternative approaches, garlic supplementation such as Aged Garlic Extract (Kyolic), can be used[i].  Other supplements that may be beneficial include: Cox 2 inhibitors such as Celebrex (Ibuprophen and similar drugs, which inhibit both Cox 1 and 2 may be equally effective) and selenium, 200 ug daily. 

Exercise in moderation stimulates the immune system, so take a walk with friend or lover.  A little sunshine is also good for you, as is a good laugh.  Don’t take any of this too seriously, but do be involved in your own care- people who are live longer.  Be sure to be happy and enjoy your extra time!

---

[i] Lamm DL and Riggs DR:  The potential application of Allium sativum (garlic) for the treatment of bladder cancer.  Urol Clin North Am 27(1): 157-162, 2000.

Health Food Store (e.g. GNC) options for phytochemical treatment of bladder cancer

1.       Sulforophane, the main phytochemical in Broccoli and other cruciferous vegetables.  Only 3 servings a month reduced bladder cancer risk by 50%, an effect now confirmed by 3 independent studies.  Recommendation: 2-3 servings of raw or lightly steamed broccoli a week.  An alternative would be 100mcg sulforophane twice a day (Nature’s Way or other, cruciferous vegetable extract softgel).

2.       S-allyl cysteine, the aqueous extract of garlic and other allium vegetables.  Aged Garlic Extract (Kyolic, by Wakanaga laboratories, Japan) was confirmed in our laboratory to reduce the incidence, growth and mortality of transplanted bladder cancer in mice.   The human dose from these experiments would be 8ml a day, but we recommend 2-4 ml a day (1/2 to one teaspoon) of the liquid preparation.  It can be added to vegetable juice such as V-8.  Alternatively 4 garlic cloves a day can be taken.  Garlic should be crushed and let stand for 10 minutes before cooking to permit enzymatic activation.

3.       Genistein, the main phytochemical in soy, is excreted into the urine in active form and kills 7/8 human bladder cancer cell lines in tissue culture.  We recommend 50mg twice a day (e.g. Natural Brand or other soy isoflavone concentrate) or 4 ounces of soy beans a day.

It is recommended to add these supplements to your diet one at a time each week.  That way if you have any side effects you will know what is causing the symptom.  The above three are thought to be most beneficial, but several others appear to have excellent activity as well, and can be taken as tolerated:

1.       Resveratrol, a phytochemical in grapes and peanuts, has beneficial effects on the cardiovascular system and prolongs life span of yeast and many animals.  It also has anti-tumor activity.  We recommend 4mg twice a day.  10 ounces of red wine, grape juice, or a comparable number of raisens  has 2 mg.

2.       Ellagic acid, the primary phytochemical in pomegranates and berries, inhibits prostate and bladder cancer cells.  We recommend 20mg twice a day, or 12 ounces of pomegranate juice.

3.       Quercetin, a phytochemical in apples and many plants, has been associated with a reduced risk of breast and lung cancer in some studies, and it inhibits cancer cell growth in culture.  200 to 500mg daily appears to be a reasonable dose.

4.       Curcumin, a phytochemical in curry, has antitumor activity.  200mg twice a day, or a hefty dose of the spice, may be beneficial.

5.       Lycopene, a phytochemical in tomatoes and red vegetables, reduces cancer cell growth and increases cancer cell death.  Preliminary studies suggest it may be beneficial in prostate cancer.  We suggest 40mg a day, the amount in a cup of marinara sauce.  Cooking, surprisingly, appears to increase lycopene.

References are available on request.

BCG SIDE EFFECTS: How long does weakness last?

Hi Dr. Lamm,

My husband has high grade bladder cancer and I would like to know how long the side effects of BCG such as weakness and fatigue can last?

-Marlene

Dear Friend,
Fatigue and malaise, similar to that we sometimes feel after a vaccination, occurs in about one in five patients receiving BCG.  Like most of the side effects, it is more common beginning after the second or third instillation.  Fever can also occur, and we consider low grade, mild fever and tiredness to be a sign that a good immune response is occurring.  Studies have found that those who develop fever have a lower risk of tumor recurrence.  Generally the symptoms last for two or three days, and gradually resolve. If your husband is still very fatigued when it is time to get the next treatment, we would consider delaying the treatment and reducing the dose.
Best regards,
Don Lamm, MD

BCG Recommendations 2012

 BCG Recommendations, 2012

Many studies, now including 3 meta-analyses, show that BCG intravesical therapy provides superior protection from tumor recurrence, and with maintenance schedules reduces disease progression, metastasis and mortality.  No other intravesical treatment has achieved these results.  Data from the EORTC now show that even patients with intermediate risk disease, when given my 3 week maintenance schedule, have significant reduction in recurrence, progression to metastasis, and cancer death.  Despite this good news there remain patients who fail to respond to BCG therapy.  Here are my current recommendations for optimal BCG therapy and management of BCG failure patients.

Patient Selection:  While BCG is effective in low grade, Ta tumors, these patients are at low risk of disease progression.  Chemotherapy is more effective in low grade than high grade tumors. Immediate postoperative chemotherapy reduces tumor recurrence by about 20% and in my double blind study Oncovite (Mission Pharmacal) 2 tabs twice a day. reduced recurrence by 40%.  Oncovite was most effective in patients with low grade, low stage disease.  With multiple recurrences of low grade tumor, however, changing from chemotherapy to BCG is appropriate because 25% of patients who develop muscle invasion begin with low grade, Ta disease.  For patients with CIS, high grade, or T1 TCC maintenance BCG is indicated.

Before BCG care should be taken to resect all visible tumor and cauterize CIS.  Immediate postoperative chemotherapy is given to further reduce tumor burden, which has been shown to be important in BCG therapy.  Two to four weeks later, BCG is begun.

BCG Technique: Patients are asked to minimize fluids after midnight so they will be able to hold BCG for two hours.  One vial of TheraCys or TICE BCG is diluted in 50cc preservative-free normal saline and instilled in the carefully emptied bladder. Both preparations are highly effective, but randomized comparison has found the TheraCys (ImmuCys outside of the US) to be more effective than TICE.  Patients are asked to lie on their abdomen for 15 minutes during the two hour retention period.  Treatments are given weekly for a total of 6 weeks.  Do not give BCG if catheterization causes bleeding or patients have cystitis.

Maintenance is given weekly for 3 weeks at 3, 6, 12, 18, 24, and 36 months.  I have omitted the 30 month treatment, but in high risk patients continue at 4, 5, 6, 8, 10 and 12 years to reduce the risk of late disease recurrence and progression.  We recommend 1/3 dose BCG during maintenance and I would recommend  further reducing to 1/10, 1/30, and 1/100^th dose in 50cc in any patient with increased side effects.  The benefit of BCG is gone 10 years after the last treatment.

BCG Failure may be caused by occult invasive or extravesical disease, inadequate immune response, or BCG resistance.  Extravesical and invasive disease should be sought and treated.  Percutaneous BCG can be given to improve response, especially in PPD skin test negative patients.  A second 6 week course of BCG should not be given unless interferon is added because immunosuppression may otherwise be induced.  50 MU is added directly to BCG, often using the reduced BCG dose.  Mitomycin 40mg/20cc, Adriamycin 50mg/25cc, Thiotepa 30mg/15cc, docetaxel 20mg/10cc or Gemcitabine 200mg/10cc water can be used in patients who are not candidates for cystectomy.  If that doesn’t work call me- we are looking at new therapies such as Eoquin, Chemophase plus Mitomycin, hyperthermic chemotherapy, combination chemotherapy, KLH, Regressin, and GMCSF producing adenovirus gene therapy.

Side Effects can be reduced by lowering the dose, giving Ofloxacin 200mg 6 hours after instillation and the following morning, or retaining BCG for only 30 minutes.  BCG infection is treated with INH 300mg/d and Cipro 500mg bid.  Serious reactions require triple antibiotics and steroids.

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).