Original article
Characterizing intermediate-risk non–muscle-invasive bladder cancer: Implications for the definition of intermediate risk and treatment strategy

https://doi.org/10.1016/j.urolonc.2016.11.014Get rights and content

Highlights

  • Intermediate-risk tumors that recurred after a high-risk should be discriminated.

  • Their recurrence rate was higher when compared with the other intermediate-risk cases.

  • Adjuvant BCG therapy may be indispensable for them.

  • BCG refractory cases had a significantly higher rate of stage progression.

  • BCG refractory tumors need to be managed as a separate category.

Abstract

Purpose

Patients with intermediate-risk non–muscle-invasive bladder cancer have traditionally been defined as those not included in the low- or high-risk groups. Therefore, the intermediate-risk group consists of heterogeneous patients.

Materials and methods

We reviewed 326 patients diagnosed with intermediate-risk tumors. We subclassified these patients into 3 groups according to their clinical courses. Group A included patients with initial and multiple low-grade tumors (N = 170). Group B consisted of patients with a low-grade tumor that recurred after a low-risk tumor (N = 97), and Group C consisted of patients with a low-grade tumor that recurred after a high-risk tumor (N = 59).

Results

The 2-year recurrence-free survival rate was significantly lower in Group C (42%) than in Groups A (69%, P<0.01) and B (70%, P<0.01). Regarding progression-free survival, no significant differences were observed among the groups. In total, 167 patients received adjuvant bacillus Calmette-Guérin (BCG), and 39 received adjuvant chemotherapy instillations. In Groups A and B, there were no significant differences in efficiency against tumor recurrence between BCG and chemotherapy. In Group C, the 5-year recurrence-free survival rate was 65% in patients receiving BCG, which was significantly higher when compared with patients receiving chemotherapy (P = 0.01). Furthermore, Group C included 11 BCG refractory cases, 5 of whom later experienced stage progression during follow-up.

Conclusion

Our subclassification analysis suggested that intermediate-risk tumors that recurred after a high-risk tumor (Group C) should be treated with adjuvant BCG therapy, owing to the high probability of subsequent recurrence. Furthermore, the definition of intermediate risk may include some BCG refractory cases.

Introduction

Stratification of low-, intermediate-, and high-risk non–muscle-invasive bladder cancer (NMIBC) has been widely employed to predict prognosis and to guide relevant adjuvant treatment. Initial and solitary pathological low-grade Ta tumors are generally defined as low-risk, and tumors of high-grade, stage pT1, or with concomitant carcinoma in situ are regarded as high risk [1], [2]. Although low- and high-risk disease have been pathologically well defined using this system, the intermediate-risk category has traditionally been defined as any patient not fitting into either of the earlier 2 categories. Therefore, intermediate-risk disease comprises a very heterogeneous population, ranging from those with a solitary, but recurrent, low-grade Ta tumor, to those with multiple low-grade Ta tumors that recurs after bacillus Calmette-Guérin (BCG) therapy. Furthermore, no guideline has clearly stated whether all patients who initially had a high-risk tumor should be treated as high risk throughout their entire lives even if they have a subsequent low-grade tumor recurrence. These cases might be reassigned to the intermediate-risk.

Thus, the recommended treatment strategies for patients with intermediate-risk disease are diverse among the current clinical practice guidelines, and do not agree with each other in some respects [3], [4], [5]. Options for intermediate-risk disease after transurethral resection of bladder tumor (TURBT) ranging from only observation without any intravesical instillations to adjuvant intravesical chemotherapy or BCG. It has also remained uncertain whether induction alone, or induction plus maintenance of intravesical chemotherapy or BCG therapy should be used for patients with intermediate-risk disease.

In the present study, we reviewed 326 patients with intermediate-risk tumors who were treated with conservative therapy and analyzed subsequent tumor recurrence and stage progression. We then classified these intermediate-risk tumors into 3 groups by clinical courses. This classification may provide a better understanding of this heterogeneous risk group, and allow practical recommendations for the management of intermediate-risk disease.

Section snippets

Patients and methods

Our risk stratification of NMIBC was based on the international bladder cancer group statements [1], [2]. We defined the intermediate-risk category as including those who did not fulfill the requirements of either the low-risk (solitary, primary low-grade, and Ta tumor) or high-risk (any high grade, stage T1, or carcinoma in situ tumors) categories. We did not include tumor size to classify the risk stratification of our patients with NMIBC. Some guidelines assigned large low-grade solitary

Patients׳ characteristics

The clinical characteristics of Groups A, B, and C are summarized in the Table. The proportion of those with a previous history of intravesical BCG adjuvant therapy just before diagnosis of the intermediate-risk tumor was 49% in Group C, which was significantly higher when compared with Group B (17%, P<0.01), and no administration of adjuvant therapy was more frequent in Group B (77%) when compared with Group C (37%, P<0.01). The interval between the prior tumor and the recurrent

Discussion

This is the first study, to the best of our knowledge, focusing on the intermediate-risk category of NMIBC. We demonstrated that this category consists of a very heterogeneous population; thus, we propose a new subclassification system of intermediate-risk NMIBCs. First, cases with a past history of high-risk NMIBC (Group C) should be discriminated from the other intermediate-risk cases (Groups A and B), because their recurrence rate was shown to be significantly higher when compared with the

Conclusions

Our subclassification analysis suggested that intermediate-risk tumors that recurred after a high-risk tumor should be treated with adjuvant BCG therapy, owing to the high probability of subsequent recurrence. In addition, the definition of intermediate risk may include some BCG refractory cases. Such BCG refractory cases had a significantly higher rate of stage progression in the present study, and we conclude that such BCG refractory tumors need to be managed as a separate category.

References (21)

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Cited by (5)

  • Significance of Bladder Neck Involvement in Risk Substratification of Intermediate-Risk Non–muscle-invasive Bladder Cancer

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    Several previous studies reported the risk substratification of intermediate-risk NMIBC. Matsumoto et al [20] showed that patients with a low-grade tumor that recurred after a high-risk tumor had higher recurrence rates than those with a low-grade tumor that recurred after a low-risk tumor and those with initial multiple low-grade tumors; however, progression rates were not significantly different among the three groups. IBCG recommended substratification of intermediate-risk NMIBC using an algorithm including multiple tumors, tumor size >3 cm, early recurrences (<1 yr), and frequent recurrences (>1/yr) [6,7].

  • Efficacy of Immediate Postoperative Instillation of Chemotherapy for Primary Non–Muscle-Invasive Bladder Cancer in Real-World Clinical Practice

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    Because IPIOC is indicated in most patients with NMIBC, patients with recurrent NMIBC are highly likely to have received previous intravesical chemotherapy, which might compromise the sensitivity of the tumor to further intravesical chemotherapy. Indeed, the intermediate-risk group is known to consist of a heterogeneous population.15 Further studies are required for better prognostication and prediction to stratify patients who will really benefit from IPIOC with BCG treatment.

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