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by Dr. C.H. Weaver M.D. updated 6/2021

Stage II and III bladder cancer is often referred to as muscle invasive bladder cancer (MIBC) often treated with removal of the bladder (cystectomy). Clinical studies increasingly suggest that bladder removal may be avoided in a majority of patients using a combined approach consisting of neoadjuvant chemotherapy, followed by limited surgery, immunotherapy and close surveillance.10

Patients with Stage II (T2) 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 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 classified as a “deep” or “invasive” bladder cancer.

There are essentially two ways to treat stage II -III bladder cancers: primary surgical treatment consisting of radical cystectomy with some form of urinary diversion or combined modality treatment consisting of administration of chemotherapy and/or radiation therapy, followed by radical cystectomy only for those patients who do not achieve a complete response. 

Patients who achieve a complete response following chemotherapy and/or radiation are followed closely and are treated with a radical cystectomy if cancer returns. It is important to realize that several physicians, including a urologist, a medical oncologist, and a radiation oncologist may be required to assist you in making the appropriate decision concerning the initial choice of treatment for stage II - III bladder cancer.

The general health condition of the patient may help determine which approach to treatment is most appropriate. It is important to consider whether the patient is well enough to undergo radical cystectomy and creation of an artificial bladder. It is the general health condition, rather than age, that can be the limiting factor for this type of surgery. For patients in good condition, the choice will depend on the extent of cancer and the preferences of the patient and treating physicians.

Surgery as Primary Treatment

Radical cystectomy is a standard treatment for invasive bladder cancer. A radical cystectomy involves removal of the bladder, tissue around the bladder, the prostate, and seminal vesicles in men and the uterus, fallopian tubes, ovaries, anterior vaginal wall, and urethra in women. In addition, a radical cystectomy may or may not be accompanied by pelvic lymph node dissection. Radical cystectomy was once considered a procedure that seriously affected a patient’s quality of life. With the creation of artificial bladders, referred to as continent reservoirs or “neobladders,” that preserve voiding function, a radical cystectomy is now a far more acceptable procedure.

Segmental cystectomy (partial removal of the bladder) may be appropriate therapy in some patients with smaller cancers. In some cases, stage II bladder cancer may also be controlled by transurethral resection (TUR) if the cancer is small enough and does not extend far into the bladder wall. A 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.

Approximately 50-80% of patients with stage II - III bladder cancer are cured after undergoing a radical cystectomy.

To learn more about TUR and cystectomy, go to Surgery for Bladder Cancer

Systemic Therapy Prior to Cystectomy (Neoadjuvant Therapy)

Following a radical cystectomy, local recurrence of cancer is uncommon because the cancer and bladder are removed. Some patients however will still develop distant recurrences because undetected cancer cells called micrometastases spread to other locations in the body before the bladder was removed. Treatment with a systemic (whole-body) therapy such as chemotherapy or immunotherapy may reduce or eliminate these micrometastases reducing the risk of cancer recurrence and avoid cystectomy. 

Neoadjuvant therapy refers to systemic therapy that is given before surgery. The rationale behind neoadjuvant therapy for bladder cancer is twofold. First, pre-operative treatment can shrink some bladder cancers and therefore, may allow more complete surgical removal of the cancer. Second, because systemic therapy kills undetectable cancer cells in the body, it may help prevent the spread of cancer when used initially rather than waiting for patient recovery following the surgical procedure.

A study published in the New England Journal of Medicine reported that patients with muscle-invasive bladder cancer who received chemotherapy prior to cystectomy had better survival than patients treated with cystectomy alone.1

Adjuvant Therapy After Surgery

Adjuvant therapy is a systemic treatment that follows surgical cystectomy. Clinical trials have compared adjuvant chemotherapy to no additional treatment in advanced bladder cancer and found that cystectomy plus adjuvant chemotherapy improves survival compared to treatment with cystectomy alone.2 One study also suggests that adjuvant therapy should not be delayed. The study found that immediate treatment (< 90 days) from cystectomy delayed cancer progression and improved survival.3

Immunotherapy treatment appears to play a role in the managemnt of stage bladder cancer. The checkpoint inhibitor Opdivo (nivolumab) has been reported to significantly delayed the time to cancer recurrence following surgery. Opdivo treated patients survived on average 21 months without cancer recurrence compared to 10.9 months for those receiving placebo. Overall therapy was well tolerated, and the most common treatment-related side effects were diarrhea, colitis, and pneumonitis.9

Can Cystectomy Be Avoided in Muscle-Invasive Bladder Cancer

The answer is yes for many patients. Radical cystectomy is a major operation and requires diversion of the urinary stream, which has life-altering implications. Identification of patients that can have their cancer eradicated with transurethral resection plus systemic therapy alone and avoid cystectomy is a priority. Transurethral resection of bladder tumor (TURBT) plus systemic therapy has been known for decades to achieve durable bladder-intact survival in a subset of patients. Research presented at the 2021 America Society of Clinical Oncology Annual Meeting defined an approach using Gemzar (gemcitabine), cisplatin chemotherapy combined with Opdivo immunotherapy designed to preserve the bladder in as many patients as possible.

Researchers initially treated patients with with 4 cycles of Gemzar, cisplatin, plus Opdivo immunotherapy followed by clinical re-staging to determine next steps. Re-staging was comprehensive and included urine cytology, MRI/CT of the bladder, cystoscopy, and bladder/prostatic urethral biopsies. Patients achieving a clinical complete response were eligible to proceed without cystectomy and receive Opdivo every 2 weeks and close surveillance; otherwise, patients underwent cystectomy. If local recurrence occurred patients proceeded to cystectomy. This approach allowed a majority of patients with MIBC to avoid cystectomy.10

Maintenance Bavencio Prolongs Survival: 

In 2017, the FDA approved Bavencio for the treatment of patients with locally advanced or metastatic bladder carcinoma. The JAVELIN Bladder 100 clinical trial compared maintenance Bavencio plus best supportive care (BSC) to BSC alone in patients with locally advanced or metastatic bladder cancer. A total of 700 patients whose disease had not progressed after induction chemotherapy were treated with either Bavencio plus BSC or BSC alone. The median overall survival improved from 14.3 months to 21.4 months when Bavencio was added to supportive care.9

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Chemotherapy and Radiation Therapy for Primary Treatment

Over the past decade, there have been many clinical trials in the United States and Europe evaluating the combination of radiation and chemotherapy for 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 achieve a complete response to treatment can often avoid additional treatment with a radical cystectomy unless they experience recurrence of their cancer.

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 for three to four years after treatment. These results appear as good as those observed with radical cystectomy, but there have been no direct comparisons between bladder-preserving therapy and radical cystectomy. While bladder-preserving therapy has been widely adopted for the treatment of stage II bladder cancer, some physicians still think it should be limited to clinical trials and not adopted as standard therapy.

Chemotherapy Alone as Primary Treatment

Treatment with chemotherapy alone is less effective than combined approaches to treatment.4

Radiation Therapy Alone as Primary Treatment

Currently, the use of radiation therapy alone has been replaced by the use of radiation therapy and chemotherapy. However, there may be some patients who cannot tolerate chemotherapy, and radiation alone could be beneficial.

To learn more, go to Radiation Therapy for Bladder Cancer.

Questions to Ask Your Physician About the Treatment of Stage II-III Bladder Cancer

  • What are the long-term results of treatment with radical cystectomy at the treating institution?
  • What is the quality of life with the type of artificial bladder constructed at the treating institution?
  • What are the long-term results of bladder-sparing treatments at the treating institution?
  • How will systemic therapy improve my outcome compared to treatment with surgery alone?
  • Can MRD assessment be used to improve treatment?

Strategies to Improve Treatment

Most new treatments are developed in clinical trials. The development of more effective cancer treatment for bladder cancer requires that new and innovative therapies be evaluated in patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of bladder cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits with their physician.

MRD Assessment

Bladder cancer patients with residual cancer following surgery are known to be at the highest risk of recurrence, and patients without residual disease are less likely to benefit from additional treatment. A test that could accurately identify the presence of minimal residual disease(MRD) and predict which patients benefit from additional could help patients avoid unnecessary treatments and would be of great value. Several MRD tests are about to become available. The Signatera MRD test is one such test and is unique in that it is personalized.

Muscle invasive bladder cancer carries a substantial risk of recurrence and/or death because nearly 50 percent of patients develop recurrence within two years of cystectomy (the surgery to remove the bladder). Patients with muscle invasive urothelial (bladder) cancer and evidence of circulating cancer cell DNA (ctDNA) following surgical removal of visible cancer are known to have high risk of disease recurrence following cystectomy. However, these patients experience improved clinical outcomes when treated with adjuvant Tecentriq® (atezolizumab) immunotherapy when compared to patients undergoing observation, according to results from the IMvigor010 clinical trial presented at the European Medical Oncology Society Annual Meeting in December 2020.11,12

Researchers evaluated ctDNA data from patients with muscle invasive bladder cancer enrolled in the Phase III IMvigor010 clinical trial using the Natera™ Signatera™ assay using blood samples obtained at a median of 11 weeks following surgery in 581 patients.

Thirty-seven percent of patients were determined to be ctDNA-positive, and the study found an association between ctDNA-positive patients and survival without cancer recurrence in Tecentriq treated patients compared to patients not treated with adjuvant therapy. The overall survival of ctDNA-positive patients was improved to 26 months for Tecentriq treated patients compared to only 16 months if Tecentriq was not administered. Patients who were ctDNA-negative did not benefit from Tecentriq treatment.

The study authors concluded that these findings demonstrate that post-surgical ctDNA positivity can identify which patients with muscle invasive bladder cancer are likely to benefit from adjuvant Tecentriq immunotherapy and immunotherpay can be avoided in ctDNA-negative patients.

A confirmatory clinical trial, “A Study of Atezolizumab Versus Placebo as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Bladder Cancer Who Are ctDNA Positive Following Cystectomy (IMvigor011)” ) is ongoing. The trial evaluates whether adjuvant Tecentriq immunotherapy provides benefit in patients with PD-L1-positive, muscle invasive bladder cancer who are MRD-positive within 20 weeks post-surgery based on Natera's ctDNA test.13

Precision Cancer Medicines & Immunotherapy 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. 

There are several PD-1 and PD-L1 inhibitors that work in bladder cancer and they are collectively referred to as “checkpoint inhibitors”. Checkpoint inhibitors create their anti-cancer effect 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.5-8

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

References:

  1. Grossman HB, Natale RB, Tangen CM et al. Neoadjuvant Chemotherapy Plus Cystectomy Compared with Cystectomy Alone for Locally Advanced Bladder Cancer. New England Journal of Medicine 2003.239:859-66.
  2. Galsky MD, Stensland K, Moshier EL, et al. Comparative Effectiveness of Adjuvant Chemotherapy (AC) versus Observation in Patients with ? Pt3 and/or Pn+ Bladder Cancer (BCa). Presented at the 2015 Genitourinary Cancers Symposium. Journal of Clinical Oncology. 2015; 33 (supplement 7; abstract 292).
  3. Sternberg CN, Skoneczna IA, Kerst JM, et al. Final results of EORTC intergroup randomized phase III trial comparing immediate versus deferred chemotherapy after radical cystectomy in patients with pT3T4 and/or N+ M0 transitional cell carcinoma (TCC) of the bladder. Journal of Clinical Oncology. 32:5s, 2014 (suppl; abstr 4500).
  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology.™ Bladder Cancer. V.2.2008. © National Comprehensive Cancer Network, Inc. 2008. NCCN and NATIONAL COMPREHENSIVE CANCER NETWORK are registered trademarks of National Comprehensive Cancer Network, Inc.
  5. Merck’s KEYNOTE-045 Studying KEYTRUDA® (pembrolizumab) in Advanced Bladder Cancer (Urothelial Cancer) Meets Primary Endpoint and Stops Early
  6. United States Food and Drug Administration. (2016.) News Release. FDA approves new, targeted treatment for bladder cancer.
  7. Durvalumab (Imfinzi)
  8. FDA approves new, targeted treatment for bladder cancer.
  9. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment 
  10. https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.4500
  11. Powles T, Assaf ZJ, Davarpanah N, et al. Clinical outcomes in post-operative ctDNA-positive muscle-invasive urothelial carcinoma (MIUC) patients after atezolizumab adjuvant therapy. ESMO Immuno-Oncology Virtual Congress 2020
  12. SURVIVAL ACCORDING CIRCULATING TUMOUR DNA STATUS IN THE STUDY OF ADJUVANT ATEZOLIZUMAB FOR HIGH-RISK MUSCLE INVASIVE UROTHELIAL CANCER
  13. https://www.nature.com/articles/s41586-021-03642-9