Optimal management of high-risk T1G3 bladder cancer: a decision analysis

Abstract

Background: Controversy exists about the most appropriate treatment for high-risk superficial (stage T1; grade G3) bladder cancer. Immediate cystectomy offers the best chance for survival but may be associated with an impaired quality of life compared with conservative therapy. We estimated life expectancy (LE) and quality-adjusted life expectancy (QALE) for both of these treatments for men and women of different ages and comorbidity levels.

Methods and findings: We evaluated two treatment strategies for high-risk, T1G3 bladder cancer using a decision-analytic Markov model: (1) Immediate cystectomy with neobladder creation versus (2) conservative management with intravesical bacillus Calmette-Guérin (BCG) and delayed cystectomy in individuals with resistant or progressive disease. Probabilities and utilities were derived from published literature where available, and otherwise from expert opinion. Extensive sensitivity analyses were conducted to identify variables most likely to influence the decision. Structural sensitivity analyses modifying the base case definition and the triggers for cystectomy in the conservative therapy arm were also explored. Probabilistic sensitivity analysis was used to assess the joint uncertainty of all variables simultaneously and the uncertainty in the base case results. External validation of model outputs was performed by comparing model-predicted survival rates with independent published literature. The mean LE of a 60-y-old male was 14.3 y for immediate cystectomy and 13.6 y with conservative management. With the addition of utilities, the immediate cystectomy strategy yielded a mean QALE of 12.32 y and remained preferred over conservative therapy by 0.35 y. Worsening patient comorbidity diminished the benefit of early cystectomy but altered the LE-based preferred treatment only for patients over age 70 y and the QALE-based preferred treatment for patients over age 65 y. Sensitivity analyses revealed that patients over the age of 70 y or those strongly averse to loss of sexual function, gastrointestinal dysfunction, or life without a bladder have a higher QALE with conservative therapy. The results of structural or probabilistic sensitivity analyses did not change the preferred treatment option. Model-predicted overall and disease-specific survival rates were similar to those reported in published studies, suggesting external validity.

Conclusions: Our model is, to our knowledge, the first of its kind in bladder cancer, and demonstrated that younger patients with high-risk T1G3 bladder had a higher LE and QALE with immediate cystectomy. The decision to pursue immediate cystectomy versus conservative therapy should be based on discussions that consider patient age, comorbid status, and an individual's preference for particular postcystectomy health states. Patients over the age of 70 y or those who place high value on sexual function, gastrointestinal function, or bladder preservation may benefit from a more conservative initial therapeutic approach.

Figure 1. State Transition Diagrams for Immediate Cystectomy (A) and Conservative Therapy with BCG (B)

Abbreviations: GI comp, gastrointestinal complications (diarrhea, abdominal pain, or metabolic complications secondary to ileal resection); GU comp, genitourinary complications (incontinence, sepsis, ureteral stenosis, or recurrent urinary tract infections); Mets, metastases; SEX comp, sexual complications (impotence).

Figure 2. Box Plots of Incremental Gain in LE and QALE with Immediate Cystectomy by Age for Male (Upper Plot) and Female Patients (Lower Plot)

The region in the shaded boxes of both plots represents the interquartile range. The solid line within boxes is the median incremental gain, whereas the mean value is presented as an “×”. Upper and lower whiskers indicate the 10th and 90th percentiles, respectively.

Figure 3. Box Plot of Gain in LE with Immediate Cystectomy by Age and Comorbid Status for Male Patients

The region in the shaded boxes represents the interquartile range. The solid line within boxes is the median incremental gain, whereas the mean value is presented as an asterisk. Upper and lower whiskers indicate the 10th and 90th percentiles, respectively.

Figure 4. Box plot of Gain in QALE with Immediate Cystectomy by Age and Comorbid Status for Male Patients

The region in the shaded boxes represents the interquartile range. The solid line within boxes is the median incremental gain, whereas the mean value is presented as an asterisk. Upper and lower whiskers indicate the 10th and 90th percentiles, respectively.

Figure 5. Incremental QALE Gains for the Base Case

The histogram depicts the distribution of results of 1,000 Monte Carlo simulations for 60-y-old male patients without comorbidity. Positive values indicate a larger QALE for immediate cystectomy as compared to conservative therapy. The distribution is skewed to the left.