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Originally published as JCO Early Release 10.1200/JCO.2003.01.089 on October 27 2003 © 2003 American Society for Clinical Oncology Multicentric Study Comparing Intravesical Chemotherapy Alone and With Local Microwave Hyperthermia for Prophylaxis of Recurrence of Superficial Transitional Cell CarcinomaFrom the Department of Urology, University Vita-Salute San Raffaele, Milan, Italy; the Department of Urology, Beilinson Hospital, Tel Aviv, Israel; and the University of Palermo, Palermo, Italy. Address reprint requests to Renzo Colombo, MD, Department of Urology, University Vita-Salute, San Raffaele Hospital, Via Olgettina 60, 20132 Milan, Italy; e-mail: renzo.colombo{at}hsr.it.
Purpose: To compare the efficacy and local toxicity of the intravesical instillation of a cytostatic drug versus the same cytostatic agent in combination with local hyperthermia as an adjuvant treatment, after complete transurethral resection (TURB) of superficial transitional cell carcinoma (TCC) of the bladder. Patients and Methods: The study was designed as a prospective, multicentric, randomized trial. Eighty-three patients suffering from primary or recurrent superficial (Ta-T1) TCC of the bladder, after a complete TURB, were randomly assigned to receive intravesical instillations of mitomycin C (MMC) alone, for 41 patients, and MMC in combination with local microwave-induced hyperthermia, for 42 patients. For the combined approach, a new system, Synergo101–1 (Medical Enterprises, Amsterdam, the Netherlands) was used. The effectiveness evaluation end points of the study were evaluation of recurrence-free survival and the estimated probability of recurrence. The safety evaluation end points included subjective and objective side effects and clinical complications. For the efficacy end point, Kaplan-Meier analysis was employed, with the log-rank test for significance. Minimum follow-up time was 24 months. Results: Of the 83 randomly assigned patients, 75 completed the study according to the protocol and had valid cystoscopy results. Survival analysis of the 75 assessable patients demonstrated a highly significant difference in the survival curves in favor of thermochemotherapy. Subjective intolerance and clinical complications were significantly higher but transient and moderate in the combined treatment group. Conclusion: In our series, endovesical thermochemotherapy appears to be more effective than standard endovesical chemotherapy as an adjuvant treatment for superficial bladder tumors at 24-month follow-up, despite an increased but acceptable local toxicity.
SUPERFICIAL TRANSITIONAL cell carcinoma (TCC) of the bladder shows a high rate of recurrence after transurethral resection (TURB) even after adjuvant intravesical chemotherapy or immunoprophylaxis.1–4 Moreover, as many as 35% of superficial TCCs will progress and become invasive following conservative treatment.5–7 Therefore, new and more effective approaches for the management of superficial bladder tumors should be developed and clinically tested. Recently, the endovesical administration of a combined regimen using a cytostatic agent and microwave-induced hyperthermia has proved to be highly effective and superior to chemotherapy alone in superficial bladder cancer.8–10 Our preliminary experience with local microwave hyperthermia in conjunction with mitomycin C (MMC; 40 mg in 40 mL) as an ablative procedure was reported in 1998.11 Overall, 19 patients with multiple tumors that were considered too extensive to be completely treated transurethrally underwent eight weekly 1-hour sessions of ablative treatment. Histology showed a complete and a partial response in nine patients (47%) and in seven patients (37%), respectively. Three patients (16%) underwent cystectomy because of poor response to treatment. To compare the efficacy of this combined approach with standard intravesical chemotherapy as an adjuvant treatment after complete transurethral resection of superficial TCC, a multicentric and randomized clinical study was carried out.
Patients From January 1994 to June 1999, 83 patients with primary or recurrent stage Ta and T1, grade G1 to G3 TCC of the bladder and treated by TURB were enrolled onto this study in three different departments of urology (San Raffaele Hospital, Milan, Italy; Beilinson Hospital, Tel Aviv, Israel; and University of Palermo, Italy). Patients affected by carcinoma in situ (CIS) concomitant with Ta or/and T1 lesions could be accepted. However, because only one patient presented with CIS associated with a T1-G2 tumor, he was included in the T1-G2 subgroup. Patients with primary single and small Ta tumors, transitional cell carcinoma of the prostatic urethra, and solitary CIS were excluded from the study. Patients suffering from large benign prostatic hyperplasia with residual urine exceeding 100 mL and patients with known allergy to MMC were also excluded.
Inclusion and Exclusion Criteria Exclusion criteria were low-risk TCC bladder cancer (ie, Ta, G1, single, primary cancer); stage higher than T1; residual tumor after complete TURB; transitional tumor of the bladder involving the prostatic urethra; primary (de novo) CIS; distant or lymph nodes metastases; urethral stricture; large benign prostatic hyperplasia or big middle lobe; postvoid residual urine level more than 100 mL; bladder capacity < 150 mL; urinary tract infection unresponsive to treatment; neurogenic, hypotonic bladder; known allergy to MMC; pretreatment with either local or systemic chemotherapy or radiotherapy during the last 3 months; and WHO performance status > 2. Ultimately, only patients with intermediate or high-risk tumors were accepted.
Before entering onto study, patients underwent complete transurethral resection of all tumors. Only patients who were tumor-free after TURB, as confirmed by a post-TURB cystoscopy, cold-cup biopsies of suspicious areas and negative urinary cytology, were recruited. Each eligible patient was informed about the aim, the expected results, and the possible side effects and complications of the treatment and was asked to sign an informed consent form approved by the ethics committee of the respective participating institution. Clinical pretreatment assessment included ultrasound evaluation of the abdomen and pelvis, uroflowmetry, and measurement of postvoid residual urine. All patients were asked to complete the detailed questionnaire shown in Table 1
Patients were then randomly assigned to either group 1 (local microwave-hyperthermia plus intravesical chemotherapy [HT + MMC] or group 2 (intravesical chemotherapy alone [MMC]). A specially designed randomization form was completed by the investigator at each clinical center and faxed to the clinical study project center. The study statistician prepared a numbered list of treatments in randomized order, for each participating clinical center. Separate, numbered, randomized treatments for each center were maintained by the project secretary in closed, numbered envelopes. The envelopes were not opened until a randomization form from a specific clinical center was received. On receipt of a randomization form, the secretary would open the next consecutive, numbered envelope and attach the content (ie, the specified treatment group) to the randomization form. The randomization form with the specified treatment group was returned to the clinical center. There were no stratification factors included in the randomization method. A total of 42.9% and 41.5% patients in group 1 and 2, respectively, had received previous intravesical treatment with bacille Calmette-Guerin or chemotherapeutic agents (MMC, epirubicin, or other) with a free interval of at least 3 months. Pretreatment cystoscopy and urinary cytology were performed 20 to 30 days after TURB. The adjuvant treatments were initiated 20 to 40 days after TURB. For both groups of patients, the treatment regimen included an induction cycle of eight weekly sessions and a subsequent maintenance regimen of four monthly sessions. The duration of each session was 60 minutes, and all sessions were performed on an outpatient basis.
Treatment All sessions were conducted on an outpatient basis with the use of an anesthetic urethral gel. Each session began by emptying the bladder of any residual urine. The operative catheter was then inserted into the bladder, and the balloon was inflated with 15 mL of distilled water. The three thermocouples were spread out to contact the bladder walls, and a solution of 20 mg MMC in 50 mL distilled water was instilled. The intravesical location of the catheter balloon, the applicator, and the thermocouples during the operative session was assessed in most cases by suprapubic ultrasound. Hyperthermia was delivered at medium temperature of 42.0°C ± 2°C for at least 40 minutes per session. To better stabilize the dose concentration of the solution in the bladder throughout the session, the solution was replaced after 30 minutes. Group 2 (MMC). Forty-one patients were randomly assigned to receive intravesical chemotherapy alone. These patients were treated using the same experimental conditions (drug dose and concentration, 20 mg MMC in 50 mL distilled water; contact time, 1 hour; schedule of administration, replacement of the solution after 30 minutes) used for group 1 patients, but hyperthermia was not delivered. A 12F to 16F Nelaton catheter was used for each single instillation.
Statistical Analysis
Pooling of study centers.
To justify pooling of the clinical data from the three participating centers, statistical analysis was performed to determine if there was a significant difference in the demographic and baseline tumor characteristics between them. This analysis was based on data from the study sample consisting of 83 patients who entered the study (ITT cohort). Any continuous data were transferred to categoric data., and the Pearson Efficacy and safety analysis. The primary efficacy analysis, which assessed time to first recurrence between the two treatment groups, was investigated using Kaplan-Meier survival analysis with the log-rank test for significance. Additionally, the Cox proportional hazards model with the Wald test for significance was used to evaluate the interaction between treatment group and center, to test if the treatment difference was consistent or not across centers. Secondary efficacy analyses included the effect of different demographic and prognostic factors on the recurrence rate, using a stratified log-rank test. The event, recurrence, was defined as a biopsy confirmed tumor recurrence observed during a follow-up cystoscopy examination. Censored patients were patients who dropped out of the study and were lost to follow-up or did not have a recurrence by the 24-month end point. The efficacy analysis were based on the per-protocol patient cohort. Crosstabulations of the local side effects, clinical complications, and intercurrent events according to severity and treatment group are provided. Fisher’s exact test for homogeneity of the side effects, complications, and intercurrent events within the groups was performed.
Assessment of Outcome Side effects and clinical complications. All patients underwent physical examination before starting each session. Blood tests, including WBC and RBC count, were performed before starting treatment, at the end of the induction cycle, and then quarterly. All patients were asked to complete the subjective symptoms questionnaire before starting treatment, at the end of the induction cycle, and 7 to 10 days after the maintenance cycle. Subjective symptoms were expressed as the mean value of the score assigned to each symptom. Uroflowmetry was performed before starting treatment, at the end of the induction cycle, and then quarterly. Clinical complications and other intercurrent events were reported in each patient’s personal file.
Of the 83 randomly assigned patients, 75 patients completed the study according to the protocol and had valid cystoscopy results. Three patients in group 1 and five patients in group 2 withdrew from the study; reasons were subjective intolerance (two patients), personal decision (two patients), and protocol violations (four patients).
Baseline Demographic and Tumor Characteristics
Efficacy Analysis Primary efficacy. Six (17.1%) and 23 (57.5%) recurrences were seen in groups 1 and 2, respectively. The results of the log-rank test clearly demonstrate a highly significant (P = .0002) difference in recurrence of tumors between the two treatment groups, where tumor recurrence in the chemotherapy alone group is significantly earlier and more frequent (Fig 1  ). The same trend was observed in all participating centers (P = .0003; Kaplan-Meier curves not presented; hazard ratio [chemotherapy alone v chemotherapy with Synergo], 4.821; 95% CI, 1.953 to 11.899). Cox regression was used to test for interaction between treatment group and clinical center. According to the Wald test, the interaction term is not significant (P = .087).
Secondary efficacy. The demographic factors age and sex had no significant effect on recurrence in either treatment group (P > .05). The analyses of the prognostic factors fail to demonstrate a significant effect of the previous tumor size (  2 cm), previous multifocal tumors ( 5; Fig 2A), and previous stage (Fig 2B) and grade of tumor on recurrence rates of the treatment groups (P > .05), though the results for previous number of tumors and for previous multifocal tumors were close to significance. In all subgroups, however, the same trend (ie, the lower recurrence rate in group 1) was uniformly evident.
The only prognostic factor that did demonstrate a significant effect on the recurrence rates of the treatment groups was history of type of recurrence (first episode [other], recurrent, or high recurrent; Fig 2C  ). The stratified log-rank test was used to test history of type of recurrence for significant effect on recurrence rates of the treatment groups within each type of recurrence group recurrence (first episode [other], recurrent, or high recurrent; Kaplan-Meier curves not shown). The significant treatment effect was consistent within the other types of recurrence groups (first episode and highly recurrent). In these groups, the chemotherapy alone group had a significantly higher rate of recurrence than did the chemotherapy and hyperthermia patient group. Previous local chemotherapy did not influence the results (Kaplan-Meier curves not shown). The total number of treatment sessions had a significant association (P < .0001) with the recurrence rates of the treatment groups. Patients who received the full number of treatment sessions (eight inductive sessions and four maintenance sessions) had a lower recurrence rate than did those patients who received less than the complete treatment protocol.
Disease Progression
Safety Analysis
Clinical complications. One complication, reduced bladder capacity with urge incontinence, was observed in the thermochemotherapy group. In this patient, the maximum bladder volume, as documented during follow-up cystoscopy, was 150 mL. Voiding patterns, as expressed by uroflowmetry and measurement of residual urine, remained unchanged in both groups. There was no significant difference in side effects and clinical complications observed in the three participating centers nor between groups.
It is well known from the literature that malignant cells are more sensitive to heat than are normal cells. Hyperthermia causes an inhibition of cellular respiration and synthesis of DNA, RNA, and proteins, blocking the cells in S phase. These injuries may be lethal to the cell if repair mechanisms are not effective. Homogeneous heating of the tumor depends on its volume, the temperature applied, and the thermal dissipation via the blood supply. When used as a monotherapy approach, local hyperthermia obtained only limited results in clinical trials.12–17 However, local hyperthermia has proved to develop a synergistic antitumor cell killing effect when used in combination with selected cytostatic agents for the treatment of many solid tumors, including transitional cell carcinoma.18–22 Superficial bladder tumors, due to their endocavitary location, have represented a model for the simultaneous administration of local hyperthermia and chemotherapy for a long time. However, the lack of suitable technology has so far strongly limited the clinical application of this regimen. After intensive laboratory and animal investigations, a novel system, based on a transurethral radiofrequency applicator, was specifically realized and clinically tested in patients with superficial TCC of the bladder. During the last decade, this system was mainly used as an alternative to TURB. When clinically used for this indication, this system was shown to be effective and safe.10,11 In a randomized trial, it was more effective than intravesical chemotherapy alone.8
The present study investigated the efficacy and safety of the thermochemotherapy regimen compared to intravesical chemotherapy alone as adjuvant treatment for superficial bladder cancer after a complete transurethral resection. Local side effects, in the form of cystitis symptoms, suprapubic pain, and thermal reaction of posterior bladder wall, were more severe in patients who underwent thermochemotherapy. However, local side effects did not influence the completion of the treatment and were transitory, asymptomatic, and self-recovering shortly after the end of therapy. The most frequent side effect was in the form of painless, superficial, confined ( These results are preliminary and need to be confirmed by larger prospective, multicentric studies. The combined treatment (HT + MMC) was more expensive and cumbersome than the routine instillation of chemotherapeutic agents or bacille Calmette-Guerin. A larger catheter must be used and its insertion becomes more invasive. However, the reduction in proportion of recurrences at 24-month follow-up in favor of the thermochemotherapy regimen encourages further clinical investigations. A long-term evaluation is already underway. An alternative interpretation of our results can be that the dose and concentration of MMC in the control arm was lower than those adopted elsewhere.23,29 This interpretation may be supported by the relatively higher recurrence rate with MMC in this study than in other series. However, Kim and Chongwook,30 using the 40 mg MMC dose in 43 patients with untoward prognostic factors (recurrent [> 3], multiple [> 3], or large [> 3 cm] tumors) reported an 81% recurrence rate at 2-year follow-up.30 We note that series displaying a lower recurrence rate usually have a different selection of patients, including those with good-risk cases, whereas in our study, only intermediate- and high-risk cases were represented (26% and 17% G3 tumors in groups 1 and 2, respectively). In our series, most tumors were recurrent, > 2 cm in diameter, and stage T1. Almost 30% displayed marked multiplicity (> five tumors). A dose of 20 mg of MMC for 1 hour may be suboptimal. However, a MEDLINE search combining the keywords "MMC" and "bladder instillation" showed a total of 120 articles, published between 1991 and 2001, 40 of which were particularly relevant and gave sufficient details. Although few articles mention 60 mg of MMC as a possible dose for prophylactic treatment, no results are given for this dose, and a warning is given that higher doses can increase the incidence and severity of side effects. Looking only at published results, of the 40 studies, 16 studies (40%) used the 20 mg dose, eight studies (20%) used the 30 mg dose, and 16 studies (40%) used the 40 mg dose. According to the manufacture’s labeling, the recommended dose is 40 mg for intravesical instillation, and the European Urological Association guidelines31 recommend 20 to 40 mg as the standard dose of MMC. Therefore, 20 mg is a widely accepted dose, recommended within a range of standard doses by many authorities.32–38 Au et al39 addressed the issue of adequate drug delivery to enhance the prophylactic efficacy of MMC. They compared the efficacy of an optimized 40 mg MMC dose regimen with that of a standard regimen commonly used in their community (20 mg). They introduced different variables, such as minimizing residual urine, reducing urine production during the instillation period, and alkalinizing the urine, so that the significance of the dose factor cannot be singled out, because of the many additional factors.40–42 Our schedule involves changing the MMC solution after 30 minutes to reduce the dilution factor because of continuous production of urine during the contact time between the bladder wall and the MMC solution. We believe this will compensate for what may appear to be a more diluted solution (20 mg in 50 mL) compared with other commonly adopted schedules, in which the original dose is diluted during retention time by the continuous flow of urine into the bladder. Even if a more efficacious control arm can be envisaged, this study shows that the addition of hyperthermia to a commonly used MMC instillation schedule does improve the clinical outcomes when compared with MMC alone, using the same experimental conditions. As far as higher concentrations of MMC combined with thermochemotherapy are concerned, in two different trials designed to assess the efficacy and safety of endovesical thermochemotherapy when used for TCC ablation, an MMC dose concentration of 40 mg in 50 mL of distilled water was used. In that clinical experience, the higher dose of MMC was similarly well tolerated with only a slight increase of local side effects.8,10,11 To confirm these clinical findings, we also conducted a clinical trial designed to asses the absorption rate of MMC in combination with microwave hyperthermia. According to this study, a dosage concentration of MMC 40 mg in 50 mL was related to a higher absorption rate of the drug; that, however, remained strongly below the accepted threshold for MMC-induced side effects.43 In conclusion, this new technique appears to be useful, not only as an ablative procedure of multiple tumors as an alternative to cystectomy in selected cases, but also for the prevention of recurrence, in patients belonging to the moderate- or high-risk categories and presenting rapid and frequent recurrences despite standard treatment.
The authors indicated no potential conflicts of interest.
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40. Dalton JT, Wientjes MG, Badalament RA, et al: Pharmacokinetis of intravesical mitomycin C in superficial bladder cancer patients. Cancer Res 51:5144–5152, 1991 41. Wientjes MG, Badalament RA, Au JL: Use of pharmacologic data and computer simulations to design an efficacy trials of intravesical mitomycin C therapy for superficial bladder cancer. Cancer Chemother Pharmacol 32:255–262, 1993[CrossRef][Medline] 42. Gao X, Au JL, Badalament RA, et al: Bladder tissue uptake of mitomycin C during intravesical therapy is linear with drug concentration in urine. Clin Cancer Res 4:139–143, 1998[Abstract] 43. Paroni R, Salonia A, Lev A, et al: Effect of local hyperthermia of the bladder on mytomicin C pharmacokinetics during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma. Br J Pharmacol 52:273–278, 2001[CrossRef] Submitted January 18, 2002; accepted July 23, 2003. This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to asses statistical significance. 
5 or > 5 locations). The most important point is that there was no significant difference between the treatment groups regarding any demographic or baseline tumor characteristics (P > .05). 
