DOI of original article: 10.1016/j.eururo.2005.12.029

Ofer N. Gofrit , Dov Pode, Adi Lazar, Ran Katz, Amos Shapiro, 

Department of Urology, Hadassah University Medical Center, Jerusalem, Israel

Abstract

Objective: To determine the outcome of a watchful waiting policy in patients suffering from small, recurrent, papillary bladder tumors.

Methods: Watchful waiting has been considered an option when a small (<10 mm) papillary, asymptomatic tumor with negative urinary cytology was found on follow-up cystoscopy in patients who had previous resection( s) of superficial, low-grade (Ta) bladder tumor(s). The watchful waiting protocol included cystoscopy and urinary cytology every 3 months for 2 years (and then every 6 months). Surveillance was stopped if the patient had developed either symptoms related to the tumor or positive cytology, or if there had been a significant alteration in tumor morphology or size.

Results: Thirty-eight watchful waiting periods were documented in 28 patients (mean age 67.7 years). Mean period length was 13.5 months (SD 14.4 months; range 3-60 months). Thirty periods were terminated with tumor resection. The main reasons for termination of surveillance were the appearance of additional tumors (19 patients) and excessive tumor growth (9 patients). Hematuria indicated tumor removal in only one patient. All resected tumors were stage Ta (23 were grade 1, and 7, grade 2). The rate of tumor growth during the watchful waiting period depended highly on the tumor’s largest diameter at the beginning of surveillance. If the initial tumor diameter was smaller than 5 mm (32 cases), the tumor growth rate was 4 ± 5.1 mm3/mo (mean ± SD); if the initial tumor diameter was ≥ 5 mm (6 cases), the tumor growth rate was 870 ± 1116mm3/mo ( p < 0.05).

Conclusions: Small, recurrent papillary bladder tumors after resection of low-grade Ta tumor(s) pose minimal risk for the patient. A watchful waiting policy— without resection of the tumor—may be considered in these patients.

1. Introduction

Because of the high recurrence rate of bladder tumors after transurethral resection, a surveillance protocol is recommended to all patients [1]. When a tumor recurs, most authorities recommend its immediate removal. Therefore, many patients invariably undergo multiple transurethral resections to manage small, recurrent tumors. This approach has many disadvantages: It poses physical, emotional and economical burden on the patient, and it induces additive damage to the bladder. Surgery may be associated with complications, and, more importantly, it does not reduce the risk for further tumor recurrences. There is no proof that this type of surgery improves patients’ longevity. Is it mandatory to remove any recurrent bladder tumor as soon as it is found, or is it possible to delay surgery for a while, and refer the patient to a watchful waiting protocol?

The natural history of low-risk bladder tumors is well established, and the rates of progression and mortality from bladder cancer in patients with this type of tumor are extremely low [2,3]. Additional evidence to support the benign behavior of low-risk bladder cancer comes from trials employing marker lesions. In a combined series of 3 EORTC studies (30864, 30869 and 30952), a marker lesion was left in place for 8–10 weeks in 185 patients with low-risk or intermediate-risk bladder cancer. There were no cases of tumor progression [4].

Effective follow-up with flexible cystoscopy and urinary cytology is readily available in most institutions, and an experienced urologist can predict tumor histology accurately by just looking at it. Herr et al. reported that cystoscopy when associated with negative urine cytology correctly predicted tumor stage and grade in 99% of the stage Ta grade 1 lesions [5]. Satoh et al. showed that cystoscopic findings accurately predict muscle invasion [6].

Soloway et al., reported on a heterogeneous series of 32 patients with a history of stage Ta or T1 bladder cancer who developed tumor recurrence and were not operated on immediately [7]. The authors found that the growth rate of these tumors is slow. Tumor progression from low-grade, noninvasive (TaG1 or G2) to high-grade Ta or to T1 tumors has occurred in only 3 patients, and no cases of disease progression to T2 were found.

We report on a homogeneous series of patients with a history of low-grade Ta bladder tumors only and negative urinary cytology who developed tumor recurrence and were not operated on immediately.

2. Materials and methods

Watchful waiting has been considered an option in patients with recurrent tumors since 1996. The initial intention of this policy was to provide a framework for patients who developed recurrent bladder tumor(s) and were at a high risk for anesthesia. Since 2000, watchful waiting also was offered to patients who were not at a high risk for anesthesia. The inclusion criteria for the surveillance protocol are listed in Table 1. The protocol included cystoscopy and urinary cytology every 3 months for 2 years and every 6 moths thereafter.

Surveillance was stopped and the tumor resected in the following conditions:

1. The patient had developed symptoms related to the tumor.
2. The patient had developed positive cytology.
3. A significant change in tumor morphology was found (emergence of solid, non-papillary tumor; emergence of additional tumors).

4. Tumor growth >10 mm.

We evaluated the fate of the patients who participated in the watchful waiting protocol. Tumor stage and grade before the observation interval were compared with the pathology of the observed tumor(s) after eventual resection. Several patients underwent a number of observation periods that were analyzed separately. Histological grading was performed according to the World Health Organization and International Pathology Consensus Committee 1988, and staging according to the 2002 TNM classification of urinary bladder cancer. Tumor growth rate was based on estimates of tumor diameters documented after each cystoscopy. Tumor volume was calculated with the use of the formula: Volume = D1*D22/ 2, where D1 is the tumor’s largest diameter and D2 its smallest diameter. The Student t test (2-tailed) was used for statistical comparison. A p value <0.05 was considered statistically significant.

3. Results

Thirty-eight periods of watchful waiting were documented in 28 patients, including 6 women and 22 men, with a mean age of 67.7 years (SD 11.2 years). The mean number of transurethral

resections before the watchful waiting period was 4.1 (SD 2.7; range 1–13). All previously resected tumors were stage Ta, with a highest grade of G1 in 10 patients and G2 in 18. Previous intravesical adjuvant chemotherapy or immunotherapy was given to 18 patients. Watchful waiting was started after a mean period of 18 months (SD 18 months) after the last transurethral resection, and 69 months (SD 55 months) after each patient’s first transurethral resection. Mean watchful waiting period for all patients was 13.5 months (SD 14.4 months; range 3–60 months). Patients were followed for 1 to 5 periods. At the time of data collection, 8 patients were still under surveillance with stable unresected tumors. Thirty watchful waiting periods were terminated with tumor resection. The median follow-up of patients who were still under surveillance was 9 month, and the median follow-up of patients who underwent tumor resection was 8 months. The two periods are similar ( p = 0.56). The reasons for surveillance termination were appearance of additional tumors in 19 patients, excessive tumor growth in 9 patients, and hematuria and the need for prostatectomy each in a single patient. All resected tumors were stage Ta. Grade G1 was found on 23 occasions and grade G2 on 7.

The rate of tumor growth during the watchful waiting period was highly dependent on the tumor’s largest diameter at the beginning of the period. In 6 cases, initial tumor diameter was ≥5mm; it was 6 ± 2 mm(mean ± SD) at the beginning of follow-up and 28 ± 13.8mm at the end. Tumor growth rate in this group was 870 ± 1116mm3/mo. In 32 cases, the initial tumor diameter was <5 mm; it was 2.5 ± 0.7 mm at the beginning of follow-up and 4.6 ± 1.8 mm at the end. Tumor growth rate in this group was 4 ± 5.1 mm3/mo. The difference between the groups is statistically significant ( p < 0.05).

4. Discussion

The identification of high-risk patients is a major challenge in oncology. Almost equally important is the identification of low-risk groups, since aggressive therapy may be spared in these patients. Watchful waiting is an accepted policy in several low-risk conditions in oncology, such as prostate cancer and small renal tumors in elderly patients, and in clinical stage I non-seminomatous germ cell tumors [8–11]. The natural history of superficial, low-grade bladder cancer is well established from long follow-up periods in numerous patients and from studies employing the marker lesion approach [2–4,12]. These tumors tend to recur but rarely progress to a higher stage or grade.

Practicing urologists often face a situation in which recurrent bladder tumors are found on routine cystoscopy but cannot be immediately removed because of high risk of anesthesia. These patients often are observed by periodic cystoscopies; complications in this approach are rare. Soloway et al. were the first (and only) authors to report on a series of patients with recurrent bladder tumors that were observed for various periods and not operated on immediately [7]. In a heterogeneous series of 32 patients with a history of stage Ta or T1 bladder cancer and a mean observation period of 10 months, they found that tumor growth rate is slow (1.77 mm per month). Tumor progression from low grade, non-invasive (TaG1 or G2) to a high-grade Ta or to a T1 tumor has occurred in only three of their patients. In the current study, only low-risk patients were included (history of Ta, G1-2, only). Thirty-eight watchful waiting periods in 28 patients were evaluated, and the mean follow-up period was more than one year. Thirty periods were terminated with tumor resection.

All resected tumors were low-grade stage Ta, and there were no cases of tumor progression. The most frequent reason for termination of surveillance was the appearance of additional tumors (19/30 events). This finding means that, if an immediate transurethral tumor resection been done as soon as tumor recurrence was diagnosed, another transurethral resection probably would have been required later when additional tumors were found. Therefore, these patients probably were spared 19 redundant operations. It also was found that tumor growth rate is highly dependent on the tumor diameter at the beginning of the surveillance period. This finding may not be surprising, since a tumor that reached a diameter of 5 mm or more within a short period (since the last cystoscopy or last transurethral resection) has a fast growth rate. The growth rate of tumors that had an initial diameter smaller than 5 mm was very slow (4 mm3/mo).

Ablation of superficial bladder tumors does not always imply surgery. Office fulgurations of the tumor or ablation by intravesical administration of cytotoxic agents are two documented modalities [13,14]. Office fulguration of small tumors is effective and can be performed under local anesthesia. However, it does not provide pathology and destroys the opportunity to obtain pathology from the tumor in the future. Weekly administration of gemcitabine for six weeks destructed 56% of the treated tumors in one study [14]. Thismodality is expensive and not without side effects. It may be more suitable for intermediate-risk bladder tumors, but may be an over-treatment for small, recurrent, low-risk tumors. On the basis of the results of the current series and the results reported by Soloway et al. [7], we suggest that a watchful waiting policy can be practiced in patients fulfilling the criteria presented in Table 1.

An upper diameter limit of 5 mm may be preferred, since these tumors have a very slow growth rate. However, when significant risk of anesthesia is present, a 10mm upper limit also may be considered. In conclusion, the watchful waiting approach is reasonable in patients presenting with small, recurrent papillary bladder cancer after resection of low-grade Ta tumor(s). Many surgeries can be spared, and the risk for tumor progression in these patients is minimal. Whenever a significant change in tumor morphology or size is noted, the patient should be referred for a standard transurethral resection of the tumor.

References
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[2] Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J, Palou J, Algaba F, Vicente-Rodriguez J. Primary super- ficial bladder cancer risk groups according to progression, mortality and recurrence. J Urol 2000;164:680–4.
[3] Holmang S, Andius P, Hedelin H, Wester K, Busch C, Johansson SL. Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol 2001;165:1124–8.
[4] Oosterlinck W, Bono AV, Mack D, et al. Frequency of positive biopsies after visual disappearance of super- ficial bladder cancer marker lesions. Eur Urol 2001; 40:515–7.
[5] Herr HW, Donat SM, Dalbagni G. Correlation of cystoscopy with histology of recurrent papillary tumors of the bladder. J Urol 2002;168:978–80.
[6] Satoh E, Miyao N, Tachiki H, Fujisawa Y. Prediction of muscle invasion of bladder cancer by cystoscopy. Eur Urol 2002;41:178–81.
[7] Soloway MS, Bruck DS, Kim SS. Expectantmanagement of small, recurrent, noninvasive papillary bladder tumors. J Urol 2003;170:438–41.
[8] Hardie C, Parker C, Norman A, et al. Early outcomes of active surveillance for localized prostate cancer. BJU Int 2005;95:956–60.
[9] Klotz LH. Active surveillance with selective delayed intervention using PSA doubling time for good risk prostate cancer. Eur Urol 2005;47:16–21.
[10] Sowery RD, Siemens DR. Growth characteristics of renal cortical tumors in patients managed by watchful waiting. Can J Urol 2004;11:2407–10.
[11] Heidenreich A. Clinical stage I nonseminomatous testicular germ-cell tumors: surgery or watchful waiting, still an issue? Curr Opin Urol 2002;12:427–30.
[12] Prout Jr GR, Barton BA, Griffin PP, Friedell GH. Treated history of noninvasive grade 1 transitional cell carcinoma. The National Bladder Cancer Group. J Urol 1992; 148:1413–9.
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Editorial Comment
M. Soloway, Miami, Florida, USA
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There are several reasons to avoid a formal endoscopic tumor resection in the operating room if it is acceptable medically. Time, money, and the possibility of the unexpected complication are three good reasons that immediately come to my mind. Since most of us are quite busy and therefore want to be good time managers, we simply can compare the time required to perform a flexible cystoscopy in the outpatient office setting with a trip to the operating theater. Much of the time in the operating room is taken up by patient preparation and the anesthesia team. In the United States a visit to the operating room is quite expensive. Even the simplest bladder tumor procedure requires some disposable equipment costing hundreds of dollars. I am embarrassed when I think of how much money is ‘‘wasted’’ on a tumor fulguration procedure in the operating room. Then there is the issue of the infrequent side effect from even the smallest endoscopic procedure. Shall I mention just a few possibilities: urethral trauma, bladder perforation, bleeding, spinal headache, infection, irritative bladder symptoms. And, I did not even mention patient anxiety.

The authors confirm our report (reference 7) that small, low-grade–appearing, papillary tumors of the bladder can be monitored without risk to the patient. I have no issue with in-office cautery as an alternative, and I regularly do both, depending on the size and extent of the tumors. Patients readily are educated that these neoplasms are similar to the skin tumors that they or their friends have had removed from their face and are either the lowest-grade cancer or are benign (I do not believe grade 1, Ta tumors of the bladder are capable of metastasis, although someone will surely find the one case in the last 50 years to disprove me). Some of you will say that most of these patients eventually will get to the operating room anyway, so why not proceed promptly. My answer is that, if I can either handle these small lesions in the office by cautery or observe them until their size or appearance requires an anesthetic and transurethral resection, I will provide a benefit to my patients over the long run. Few will argue the accuracy of a diagnosis of low-grade Ta, particularly in a patient with a history of several such prior tumors. When in doubt, perform a bladder wash cytology to exclude high-grade cells.

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