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Keywords:

  • adjuvant M-VAC;
  • bladder recurrence;
  • upper urinary cancer

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Objectives:  To evaluate the efficacy of adjuvant platinum based chemotherapy in upper urinary tract urothelial cancer following surgical resection in terms of survival benefit and inhibition of bladder cancer recurrence.

Methods:  Between April 1986 and August 2005, a total of 132 patients with a diagnosis of upper urinary tract urothelial cancer underwent radical nephroureterectomy with cuff of bladder at our department. A total of 46 patients (13 with pT2pN0M0 and 33 with pT3 pN0M0 transitional cell carcinoma without prior bladder cancer) were enrolled. Patients with locally advanced disease were divided into two groups: the adjuvant chemotherapy group (24 patients) who received adjuvant methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC) and the non-adjuvant chemotherapy group who did not receive adjuvant M-VAC (22 patients).

Results:  There were no statistically significant differences in patient characteristics or 10-year survival between the two groups. The recurrence rate in the non-adjuvant chemotherapy group was significantly higher than in the adjuvant chemotherapy group (log-rank test, P < 0.0001). Only non-adjuvant chemotherapy was a significant and independent risk factor (hazard ratio 6.97) for the development of intravesical recurrence (P < 0.01).

Conclusion:  Adjuvant M-VAC is an important optional adjuvant therapy and can prevent recurrent bladder tumors following surgery for upper urinary tract transitional cell carcinoma. To determine whether adjuvant chemotherapy has further benefit, a randomized study would be needed.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

In general, radical nephroureterectomy with bladder cuff resection is the recommended initial treatment for locally advanced (cT2, cT3) transitional cell carcinoma (TCC) of the upper urinary tract (UUT). The survival benefit of postoperative adjuvant chemotherapy has been evaluated previously.1–3 However, the survival benefit remains controversial because no controlled trials of adjuvant chemotherapy in UUT cancer have been carried out owing to the low incidence of TCC of the UUT.2 Moreover, the number of cases in previous reports on the suppression of bladder cancer recurrence by adjuvant systemic chemotherapy is insufficient.4

We designed a case control study to estimate both the survival benefit and the suppression effect of platinum-based adjuvant chemotherapy on bladder cancer after total nephroureterectomy with bladder cuff excision, especially in patients with pT2 and pT3 disease without previous bladder cancer. An adjuvant chemotherapy group and a conservatively treated group (receiving no additional treatment) were compared.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Between April 1986 and August 2005, ureteral cancer or renal pelvic cancer was diagnosed in 132 patients who underwent radical nephroureterectomy with bladder cuff excision (open procedure) at our Department of Urology.

Patients meeting the following criteria were enrolled in this case-control study.

  • 1
    No prior bladder cancer
  • 2
    Pathological diagnosis of TCC
  • 3
    Stage pT2 or pT3 with total nephroureterectomy and bladder cuff resection
  • 4
    No metastasis to other organs or lymph nodes (pN0, M0)
  • 5
    World Health Organization (WHO) performance status < Grade 2.

In total, 46 patients (13 with pT2 TCC and 33 with pT3) were finally included.

The M-VAC regimen (consisting of methotrexate 30 mg/m2[Days 1, 15, 22], vinblastine 3 mg/m2[Days 2, 15, 22], adriamycin 30 mg/m2[Day 2], and cisplatin 70 mg/m2[Day 2]) was given every 4 weeks after discussing the therapy with patients and obtaining their informed consent. M-VAC was started within 2 months of the operation. To avoid severe adverse side effects induced by M-VAC, advanced age (over 80 years old) and low renal function (creatinine clearance under 60 mL/min) were excluded from M-VAC.

These patients were divided into two groups: an adjuvant chemotherapy group (24 patients who received M-VAC) (enrolled between 1986 and 1996) and a non-adjuvant chemotherapy group (22 patients) (enrolled between 1997 and 2005).

Our routine protocol involved cystoscopy and urinary cytology to evaluate recurrence of bladder cancer every 3 months in the first year, every 4–6 months in the second year, every 6 months between the second and fifth years, and annually thereafter up to 10 years. Computed tomography was carried out at least once a year to monitor metastasis. Recurrence of bladder cancer and survival were estimated during the observation period.

Statistical analysis

χ2 or Fisher's test (gender, origin, grade, and pathological stage) and t-test (age, observation period) were used to assess between-group differences. Bladder cancer recurrence and survival curves were estimated using the Kaplan-Meier method and the survival curves were compared using the log-rank test. Multivariate analysis was carried out using a Cox proportional hazards regression model.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Characteristics

Characteristics of each group are shown in Table 1.

Table 1.  Patient characteristics
 Adjuvant (+)Adjuvant (−)P-value
  1. Age and observation period are expressed as median (mean ± standard deviation, range). Adjuvant (+), adjuvant chemotherapy group; adjuvant (−), non-adjuvant chemotherapy group.

Number2422 
Male/female19/515/70.39
Age67.2 (66.4 ± 7.2 ,49–78)70.4 (70.54 ± 12.0, 34–87) 
<7015100.25
≥70912 
Observation term (month)38.3 (39.0 ± 24, 2.6–120)37.2 (33.8 ± 19, 2.9–120)0.34
Pelvic/ureter/multiple7/15/27/10/50.33
G2/G315/914/80.93
pT2/pT37/176/160.88
Numbers of M-VACOne course: 80 
two courses: 7  
Three courses: 9  

There was no significant between-group difference in gender, age, observation period, tumor origin, tumor grade, and pathological stage. The number of adjuvant chemotherapy courses was one in eight cases, two in seven cases, and three in nine cases.

Even though three cycles of chemotherapy were recommended, only nine patients received all three courses because adverse events including myelosuppression, infection, and intestinal discomfort led to premature discontinuation.

Overall survival

Overall survival rate in the adjuvant chemotherapy group was 95.8% (5 years) and 87.8% (10 years). In the non-adjuvant chemotherapy group, the 5- and 10-year rates were 86.5% and 86.5%, respectively. There was no significant difference in survival between the two groups (P = 0.81) (Fig. 1).

image

Figure 1. Kaplan–Meier curves showing overall survival in the non-adjuvant group (dotted line) and adjuvant chemotherapy group (solid line).

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Bladder cancer recurrence

There was no intravesical recurrence of the cancer in 90.8%, 83.9%, and 74.5% of patients in the adjuvant group and 48.1%, 38.5%, and 38.5% of patients in the non-adjuvant group, respectively, at 2, 5, and 10 years. The recurrence rate was significantly higher in the non-adjuvant group than the adjuvant group (log-rank test, P < 0.0001) (Fig. 2).

image

Figure 2. Kaplan–Meier curves showing recurrence (and therefore non-recurrence) of bladder cancer in the non-adjuvant group (dotted line) and adjuvant chemotherapy group (solid line).

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Multivariate evaluation

Multivariate analysis was carried out using gender, age, pathological grade, location with number of cancer metastases, stage, and adjuvant chemotherapy as variables. Non-adjuvant chemotherapy was the only identified significant and independent risk factor (hazard ratio 6.97) for intravesical recurrence rate (P < 0.01). Significant difference did not depend on the number of chemotherapy courses (data not shown). No other factor was a significant risk (Table 2).

Table 2.  Multivariate results of Cox proportional hazards models showing the relative risk of bladder cancer recurrence after surgery
FactorsMultivariate analysis (Cox Hazard model)
Hazard ratio95% CIP
  1. CI, confidence interval; M-VAC, methotrexate, vinblastine, adriamycin and cisplatin chemotherapy.

Male3.550.75 to 16.80.10
≥702.520.71 to 8.950.15
≥G30.710.23 to 2.180.55
Multiple1.660.23 to 2.130.52
T30.960.29 to 3.210.97
M-VAC (−)6.971.73 to 28.00.0063 (P < 0.01)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Since bladder cancer develops in 32% (39 of 123),5 31.2%,6 36.4%,7 47.8%,8 and 48%9 of patients after radical nephroureterectomy with bladder cuff excision for advanced TCC of UPP, a strategy to prevent bladder cancer such as adjuvant therapy is needed. Unfortunately, bladder tumors appeared in 40% (two of five) of patients treated with adjuvant cisplatin,4 but the number of patients was too small to draw any conclusion. Another approach (intravesical instillation of mitomycin C [MMC] and arabinoside C [AraC]) failed to have a significant effect.10

We are the first to report that adjuvant M-VAC is suppressive for bladder cancer recurrence in pT2pN0M0 and pT3 pN0M0 patients without previous bladder cancer.

Risk factors for bladder cancer recurrence after surgery for UUT have been evaluated previously.5,11–13 Although significant risk factors for recurrence including stage and surgical procedure,11 multifocality and pathological stage,12 pathological stage,13 and pathological grade and ureteric location5 have been identified, there are still no established optimal criteria for predicting recurrence.

In our study, only absence of adjuvant chemotherapy was a significant risk factor, suggesting that adjuvant chemotherapy inhibited intravesical recurrence and thereby diminished the effect of other factors on the growth of bladder cancer.

In terms of survival benefit, cisplatin-based adjuvant chemotherapy improved overall survival compared with treatment without adjuvant chemotherapy.3 By contrast, our study on adjuvant M-VAC therapy, like previous reports on other adjuvant therapies, could not show any survival benefit.2,14 To establish the survival benefit, a new study should be designed with enough power to allow detection.

What is the main reason for the discrepancy between the suppressive effect of this therapy on bladder tumors and its survival benefit? According to Takahashi et al., seeding or intraepithelial spread is a major mechanism for the multifocal development of urothelial cancer, but the spread of tumor cells from the upper urinary tract to the bladder may involve additional and diverse genetic alterations.15 Accordingly, survival is determined by one tumor variant responsible for bladder recurrence and another responsible for metastasis. Genetic differences in the tumors may determine sensitivity to adjuvant chemotherapy.

Regarding the chemotherapy regimen, it was recently reported that paclitaxel and carboplatin may reduce the risk of distant metastasis in high risk upper urinary tract carcinoma.16 We also reported the efficacy of paclitaxel and carboplatin (Pca) chemotherapy for advanced bladder cancer. Pca dose (especially carboplatin dose) can be escalated depending on renal function (creatinine clearance), based on area under the curve (AUC), and without serious complications including severe myelosuppression.17 Insufficient residual renal function (due to one kidney remaining after surgery or old age) rules out M-VAC adjuvant chemotherapy as an option. Consequently Pca adjuvant chemotherapy may be an alternative; we have already started to investigate this possibility.

In our study, adjuvant M-VAC could suppress the recurrence of bladder cancer but offered no survival benefit. In other words, bladder cancer recurrence will be treated with only transurethral resection. If the advantage of chemotherapy is estimated on the basis of only survival benefit, then M-VAC has no advantage, but if the estimate is based on avoiding predictable surgery, then M-VAC has benefits.

Patients not receiving chemotherapy must worry about the 30–40% recurrence rate and the possibility of needing additional transurethral resection of bladder cancer. That kind of risk can increase their stress level and decrease their quality of life (QOL).

On the other hand, in the 60–70% of patients who will not develop recurrence of their bladder tumors without additional therapy, adjuvant chemotherapy is over-treatment.

We plan in the future to show patients (with the results of our study) the advantages and disadvantages of adjuvant chemotherapy, estimate its adaptability and provide assistance in treatment decision-making and influence to QOL.

In conclusion, adjuvant M-VAC chemotherapy may have the capability to prevent bladder cancer recurrence after surgical treatment for local advanced UUT cancer without metastasis. No survival benefit would be expected if prevention is not shown. A randomized trial to elucidate the efficacy of adjuvant chemotherapy in TCC of the UPP should be conducted and its design should test the effects of side effects on quality of life.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References