Muscle Invasive Bladder Cancer

Muscle invasive bladder cancer is treated in a variety of ways with primary treatment selection varying by nation. In the US, cystectomy is preferred with 90% of all muscle invasive disease. The US bladder preservation rate is 10% and is primarily reserved for patients who are medically high risk operative candidates. In Scandinavia the rate of bladder preservation rises to 25% and in the UK the rate is in excess of 50%.

Anatomy

Bladder anatomy is straightforward. The bladder consists of transitional cells which are contiguous with the ureters which enter on the posterior lower aspect at the top of the trigone of the bladder. The bladder drains via the urethra which is controlled by muscular structures in the prostate in men and well as sphincters in men and women at the uro-genital diaphragm.

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Epidemiology, Pathology, and Natural History

The epidemiologic factors include tobacco, analine dyes, aromatic amines and chlorinated hydrocarbons, and follows the same general pattern as non-muscle invasive disease. Up to 21% of Ta and 49% will die from bladder cancers. Muscle invasive bladder cancer prognosis is poor. The EORTC has a bladder cancer recurrence/progression calculator based on the following factors:

Large population based studies sugest the main determinants of survival after diagnosis are stage, grade, age and to some extent, social class. A retrospective review in Ontario of 20,000 patients found significant variations between the use of cystoscopy and radiation in different districts but also found that outcomes between the districts were no different. The study concluded that bladder sparing approaches were equivalent to surgery for invasive bladder cancer, but cystectomy free survival varied in the different districts substantially.1

In the UK, a review of cancer registry data for 458 patients with invasive bladder cancer between 1993 and 1996 demonstrated a ratio of 1:3 cystectomy:radiation, reflective of UK practice of that time. The 10 year overall survival was similar between RT and cysectomy groups at 22% and 24%. Prognostic factors for inferior outcome were female, poor performance status, hydronephrosis and increasing T stage. Treatment modality was not a factor in the prognosis.

A study at USC analyzed 1054 patients undergoing cystectomy with 5 and 10 year surival rates of 60% and 43%. On detailed analysis of this studies data, the authors included patients with non-muscle-invasive disease and excluded 112 patients referred but deemed incurable at surgery. Re-analyzing the data after removing non-invasive cases, the 5 year survival rate drops to aroudn 47% from the original 60%. Another study reports 5 and 10 year survival of 51% and 31% but included patients deemed inoperable, unlike the USC study.

The US Intergroup study of neo-adjuvant MVAC chemotherapy (methotrexate, vincristine, adriamycin, cisplatin) demonstrated a median survival of 38 months and the 5 year survival was 42% which is consistent with other studies.

Perez and Brady suggests that many of the surgical series reporting much higher survival rates included lower risk disease in their data, thus case selection may be flavoring the studies, and as such, then tend to have a "ratcheting" effect on downstream reported results.

For non-muscle-invasive disease and carcinoma in situ, a UK study demonstrated no benefit for radiotherapy. For muscle invasive disease, a subset has been identified who do poorly with radiotherapy. This subset includes:

In cases where the bladder is poorly functioning, radiation is unlikely to improve bladder function and could make things worse. CIS does not respond well to radiation and the patient will remain at risk for further bladder involvement and procedures leading ultimately to cystectomy.

Hydronephrosis is a poor prognostic indicator and is not specific to radiation, but is equally a poor prognostic indicator with surgery also. The presence (or absense) of hydronephrosis does not help select for or against bladder preservation or cystectomy, as both do relatively worse. Hydronephrosis is no more or less a contraindication to radiation as it is for surgery. Radiotherapy may help poor surgical candidates, including obese, diabetics, poor anesthesia risks. As bladder cancer is generally diagnosed in the mid-late 70s, few surgery series include patients over 80 in great percentages. There are likely a significant number who do are not offered surgery.

Treatment

Surgery

Invasive bladder cancer is lethal. If untreated over 85% die within 2 years of diagnosis. If cystectomy is performed earlier, an overall 5 year survival rate is around 80%. Surgical management is based on the following:

Surgery advocates argue that radical cystectomy also provides detailed pathologic information. However, there is weak evidence that additional adjuvant treatment is useful. Further, many articles emphasize the need for careful patient selection for cystectomy to achieve optimal results. There is less written about the best treatment course for patients who do not meet strict surgical selection criteria but still have bladder cancer.

Timing of surgery after TURBT is important and has been demonstrated that a delay of > 3 months reduces survival. Technical issues regarding cystectomy and appropriate lymph node dissection are critical to reducing local recurrence and positive surgical margins to maximize survival.

Radical cystectomy involves an en bloc removal of the pelvic lymph nodes, along with the organs anterior to the rectum (anterior exenteration).

  • Males
    • bladder, urachus, prostate, seminal vesicles, visceral peritoneum
  • Females
    • bladder, urachus, ovaries, tubes, uterus, cervix, and anterior pelvic peritoneum
  • Evidence suggests a more extended lymph node dissection may improve outcomes in both node positive and node negative disease.

True curative value of lymph node dissection is not known, but fewer nodes are seen in lower volume centers, and even in high volume centers the average nodes are < 10. Prostate preservation has been attempted, but intraprostatic urothelial cancers are identified in 23 - 54% with 29% clinically significant.

Surgical complications rates in the USC study were significant with a 28% early complication rate. The most common complications are related to the urinary diversion, which is prolonged urinary leakage. Neoadjuvant chemotherapy does not increase perioperative morbidity or mortality.

The literature emphasizes that radical cystectomy may be appropriately performed on carefully selected elderly patients, with the emphasis on "carefully selected."

The USC study reports most deaths within the first 3 years of surgery were generally attributed to cancer recurrence. With longer follow-up > 3 years, deaths were related to comorbidity.

Treatment delays in bladder cancer should be avoided. Prolonged delays may lead to more pathologically advanced disease and decreased survival in muscle-invasive disease. Patient selection for cystectomy should include those who have a higher probability of obtaining clear surgical margins. Caution should be taken in delaying therapy in patients who have not responded to conservative therapy.

For extravesical or lymph node positive disease, which is found in 20% of the USC series, no obvious survival differences were noted. Recurrence free survival at 5 and 10 years was 58% adn 55%. Lymph node recurrence was associated with a higher rate of recurrence. T3a (micro) and T3b (macro) disease did not appear to have an appreciable discrimination in risk.

Bladder Preservation Approaches: Muscle Invasive, non-metastatic

Radiation therapy as a means of organ preservation in muscle invasive bladder cancer has varying utilization around the world, from a low of 10% in the United States to 25% in Scandinavia to in excess of 50% in the UK. There are no prospective randomized trials comparing surgery with radiation. An attempt to learn this data came from the UK SPARE trial which compared sleective bladder preservation against radical cystectomy in T2/T3 muscle invasive bladder cancer. The trial as a Phase II/III trial examining the use of neoadjuvant chemotherapy response as predictor of total response. The trial closed due to poor accrual.

Radiotherapy use has declined markedly to under 10% in the United States over the past 3 decades, however, its use has remained high in the UK, at above 50%. Patients with radiologic positive nodes or metastatic disease should be managed with chemotherapy or with radiation applied to bulky disease as palliation. Patients with radiologic node-negative, muscle-invasive bladder cancer may be considered for radical radiotherapy as part of an organ preserving approach using maximal TURBT, chemotherapy and radiotherapy in a trimodality manner.

The general algorithm for radiotherapy in biopsy proven muscle invasive bladder cancer follows the following general algorithm:

  1. maximum TURBT
  2. Induction chemotherapy for 3 weeks
  3. Cystoscopy and biopsy at week 7
  4. If T0 or non-invasive disease only
    1. Consolidation chemo-radiotherapy in weeks 8-9
    2. Cystoscopy and biopsy week 17
    3. Based on Cystoscopy results:
      1. T0: surveillance
      2. Ta/Tis: intravesicular therapy
      3. T1+ disease: salvage cystectomy followed by adjuvant chemotherapy in select cases
    4. If T1+ residual disease proceed to salvage cystectomy

In the US, cystoscopy is the gold standard. In the UK, a clear difference in patterns of care is seen. The UK algorithm is not biased toward cystectomy, and does not include a treatment break. The UK treatment alternatives algorithm is as follows:

  1. Neoadjuvant chemotherapy ⇒ (Cystectomy or Radiotherapy)
  2. Definitive radiotherapy ⇒ (Salvage cystectomy (if needed) or chemotherapy (if relapse))
  3. Cystectomy → chemotherapy on relapse or adjuvant chemotherapy in selected cases.

The key differences in the UK is radiation, once selected is the primary treatment mode and is not given as a split course. We have repeated studies in other sites that indicate split course RT is not beneficial, and in some, is detrimental to curative goals. The US approach, as opposed to the UK/AUS approach is to include multiple checkpoints to allow early exit to surgery to assure a potential cure is not lost.

The UK philosophy is to do a maximum TURBT for debulking and diagnosis (including obtaining detrusor muscle), followed by radical radiotherapy. Long term bladder preservation in older series are similar to the rates of salvage cystectomy, post radiation therapy. 2/3 of the patients treated with bladder preservation retain their bladders. More recent chemotherapy plus radiotherapy series suggests a higher rate of bladder preservation with concurrent chemo-radiation with full dose radiotherapy.

Treatment Outcomes

Staging systems, surgical techniques, imaging techniques, and radiotherapy techniques have all changed over the time interval between older studies and the present. Patients who earlier would have been staged as having organ confined disease are now more accurately staged with contemporary imaging. This will result in an "improvement" as cases that were formerly staged and included in lower stages are upstaged and do better in the newer staging group.

Treatment techniques have also changed, but older techniques and staging have demonstrated good outcomes with radiotherapy, with overall survival rates of 30% at 5 years and 18% at 10 years using 55 Gy in 20 fractions at 2.75 Gy/fraction. The stage mix was 20% T1, 32% T2, 40% T3 and 8% T4. The study reported 46% tumor control at cystoscopy and is consistent with radiotherapy alone response rates.

More modern UK trials from 2000-2010 were BCON and BC2001, between 2000 and 2009. These studies included T2-T4aN0M0 with a small set of T1G3 comparing radiation to the bladder only to a total dose of either 55 Gy in 20 fractions at 2.75 Gy/fraction or 64 Gy in 32 fractions at 2 Gy/fraction. They used the same outcomes measure: acute/late toxicity, local-regional disease free survival and overall survival. The BC2001 trial also allowed a second randomization to reduced bladder volume with 80% of the isocenter dose to the uninvolved bladder (64 Gy * 0.8 = 51.2 Gy). The BC2001 trial permitted chemotherapy and neoadjuvant chemotherapy was a stratification factor. The BCON trial used inhaled carbogen (CO2 and O2) gas to increase tissue oxygenation. BC2001 used 5FU/mitomycin C. An NCIC trial used CDDP.

The trials demonstrated the majority of patients had grade 1/2 toxicity and the reduced volume randomization failed to demonstrate a reduction in overall toxicity, but when bowel volume was accounted, the volume of bowel treated was signficantly associated with toxicity risk. The amount of bowel and the dose to the bowel were associated with increased grade 3/4 toxicity. Again, as with the surgical arms, there was no increase in toxicity with neoadjuvant chemotherapy.

The patterns of toxicity differ between cystectomy and radiotherapy patients. Sexual dysfunction is more prominent in surgical cases and bowel symptoms more prominent in radiotherapy cases. Sexual function preservation was even more signfiicant given the patients in the radiotherapy series were about 10 years older than the surgical series.

Chemotherapy

Radiation ± chemotherapy was explored in an NCIC trial reported in 1996. This study compared the following arms:

The results of the NCIC trial did not demonstrate any effect on distant failure, but showed a clear and highly signficant effect on pelvic recurrence. Without radiotherapy, an earlier chemotherapy trial failed to show a difference in local, regional or distant control with neoadjuvant CDDP.

Failure Patterns

A significant number of bladder preservation patients will fail locally and move to salvage cystectomy. BC2001 demonstrates radiotherapy patterns of failure after radiation plus chemosensitization.

Palliative Treatment

Palliative radiotherapy has been explored in clinical trials. A prospective randomized trial was conducted in 500 patients with arm I: 35 Gy in 10 fractions at 3.5 Gy/fraction, arm 2: 21 Gy in 3 fractions at 7 Gy/fraction. The UK demonstrated no difference in effectiveness between the two groups at 68%, 71% for 35 Gy, 64% for 21 Gy.

Pre-operative Radiation

Several studies (most older) have used radiation in a pre-operative setting, usually to 40 Gy in 4 weeks followed by cystectomy. MDACC reported 5 year local control of 91% in the pre-operative group v. 71% in the surgery alone group, with a p=0.003. A review of retrospective and prospective studies concluded the use of pre-operative RT may improve outcomes by up to 15-20% at 5 years. The study noted that pCR of around 1/3, similar to neoadjuvant chemotherapy. There are no recent trials for neoadjuvant radiotherapy.

Post-operative Radiation

There is little randomized data on the use of post-operative adjuvant radiation. Primary indications are positive margins, tumor spillage at surgery, with an anticipated high rate of local recurrence. More trials should be considered.

Treatment Recommendations and Techniques

Patient should be treated supine, arms on chest with immobilization of the lower torso and legs. Rectum should be empty to insure minimal rectum is in the field. The bladder should be emptied. Scan at 2.5 - 3 mm cuts from the bottom of the ischial tuberosities to 3 cm above the dome of the bladder or the bottom of L5.

Volumes should incorporate diagnostic imaging with the CTV encompassing the whole bladder with a 1.5 cm expansion for the PTV. Include any extravesicular extensions plus 2 cm margin. All planning studies and treatments should be made with an empty bladder to keep treated volumes as small as possible and miniize the risk of geographic miss. In patients with significant urinary retention, either a catheter can be placed or alternatively, a repeat study can be performed which will demonstrate constancy in the bladder residual, suggesting reproducibility can be achieved.

There is no data supporting the routine irradiation of radiologically negative lymph nodes. The nodal relapse rate in the BC2001 trial was 3% with chemotherapy and 6% with radiotherapy confined to the bladder plus a margin.

Nontheless, the present NCCN guidelines (BL-H) suggest pelvic lymph nodes may be treated with the bladder to 40 - 45 Gy followed by a bladder boost while excluding, to the maximum extent possible, uninvolved bladder.

Radiation doses are generally 64 Gy at 2 Gy/fraction based on both the BC2001 and NCIC trials. Preoperative radiotherapy doses are (MSKCC) 40 Gy at 2 Gy/fraction followed by cystectomy 4 weeks after completion of radiation.

Chemotherapy with radiosensitization has been used, with MVAC, CDDP and gemcitabine. NCCN encourages concurrent chemotherapy using CDDP 100 mg/m2 or alternatively 5FU/mmC. Concurrent chemotherapy and radiation therapy should be considered as potentially curative for medically inoperable patients or local palliation for metastatic patients.

Outcomes