A Prospective, Randomized Controlled Study on the Treatment of Stage C and Stage D Prostatic Cancer with Estracyt in Combination with Other Chemotherapeutic Agents

The present study was designed to investigate the efficacy ofvarious combinations of chemotherapeutic agents in the treatmentof prostatic cancer in a group refractory to antiandrogenictherapy (Group 1) and in a previous untreated group (Group 2).Therapeutic combinations of Estracyt (E) + Peplomycin (P) +Doxorubicin (Do) and P + Do + 5 FU (F) in Group 1 and F + P,Honvan (Ds) + P and E in Group 2 were carried out. The mainobjectives of this study were estimations of the efficacy ofE and P in relation to the refractory cases of Group 1 and theefficacy of the combination E + P, in Group 2. This is the firstsuch prospective, randomized, controlled study to be carriedout in Japan in relation to prostatic cancer. The results obtainedin the present study indicated that chemotherapeutic regimensincluding E provide some enhanced efficacy, but that the efficacywith regard to refractory cases is poor (23.1–27.3%),as has been reported of studies conducted in the USA and Europe.With regard to previously untreated cases, the E + P regimenachieved a relatively higher response rate than the other treatments(72.7 vs 44.5 or 50.0%). In the comparison of survival timesand survival curves, there were no statistically significantdifferences among the various treatment subgroups. A comparisonof survival curves revealed the interesting finding that thePAP-related response showed a clear correlation to the survivalcurves of Group 2 patients.     

Effect of 8-MHz radiofrequency-capacitive regional hyperthermia with strong superficial cooling for unresectable or recurrent colorectal cancer.

A well-known disadvantage of a radiofrequency-capacitive device for deep-seated tumours is preferential heating of the subcutaneous fat tissue. The authors previously developed the hyperthermia with their own external cooling unit and achieved strong superficial cooling, and reported its usefulness for the reduction of the preferential heating. The purpose of the present study was to evaluate the effect of hyperthermia with strong superficial cooling on the treatment results for unresectable or recurrent colorectal cancers. From 1986 to 2002, 44 patients with primary unresectable or locally recurrent colorectal cancer treated with thermoradiotherapy were analysed retrospectively. The patients with obesity as a subcutaneous fat thickness more than 3 cm, a high age or other serious complications did not undergo therapy. The results were compared between 17 cases with strong superficial cooling treated after 1997 (Group A) and 27 cases without strong superficial cooling treated before 1996 (Group B). Significant differences in thermometry data of T(max), T(ave) and T(min) were noted between Groups A (45.3, 44.4 and 43.6 degrees C, respectively) and B (42.9, 42.0 and 41.1 degrees C, respectively) (p<0.01). Complete response plus partial response rates were better for Group A than for Group B (59 versus 26%, p = 0.05). Multivariate analysis by logistic regression to evaluate the effects of certain factors on complete response plus partial response was strongly correlated with strong superficial cooling (p<0.05). The median survival times for overall survival were 24.3 months for Group A and 17.1 months for Group B (p<0.05). Eight-megahertz radiofrequency-capacitive regional hyperthermia with strong superficial cooling is potentially useful for improving treatment results in unresectable or recurrent colorectal cancers.     

Microwave-induced local hyperthermia in combination with radiotherapy of human malignant tumors

Since 1976, two groups of patients have been treated with local microwave hyperthermia immediately following ionizing radiation. Group A patients had measurable multiple lesions assigned radiotherapy only, microwave hyperthermia only, or combined treatment. Ionizing radiation in 200-600 rad fractions was used 2-5 times per week to a total of 1800-4200 rad in 5-14 fractions. Group B patients had combination treatment only, with radiation fractions of 200-600 rad 2-5 times per week to a total of 2000-4800 rad total in 6-20 fractions. Both groups received hyperthermia (42-44 C) 2-3 times per week, maximum ten sessions in four weeks. The 19 patients treated have had squamous cell carcinoma, adenocarcinoma, malignant melanoma, plasmacytoma, epithelioid sarcoma, and undifferentiated carcinoma. After more than 150 hyperthermia sessions, we find: (1) local hyperthermia with microwave alone or in combination with ionizing radiation can be used with excellent normal tissue tolerance provided local tissue temperatures are carefully monitored and controlled; (2) a higher level of heat induction in tumor tissue as compared to surrounding normal tissues; (3) repeated hyperthermia at 42-43.5 C for 45 minutes per session immediately following photon irradiation yields a favorable therapeutic result, occasionally dramatic. Local microwave hyperthermia in combination with radiotherapy offers the possibility of substantial impact on clinical cancer therapy, whether of curative or palliative intent.     

Hyperthermia as a treatment for bladder cancer

Modern cancer care is characterized by a focus on organ-sparing multi-modal treatments. In the case of non-muscle-invasive bladder cancer this is particularly true; treatment is focused on reducing the frequency of low-risk recurrences and preventing high-risk progression. Deep regional hyperthermia is an oncologic therapeutic modality that can help achieve these two goals. The combination of hyperthermia with chemotherapy and radiotherapy has improved patient outcomes in several tumor types. In this review, we highlight the biology of therapeutic fever-range hyperthermia, discuss how hyperthermia is administered and dosed, demonstrate how heat can be added to other treatment regimens, and summarize the data supporting the role of hyperthermia in the management of bladder cancer.     

FGF2-mediated reciprocal tumor cell-endothelial cell interplay contributes to the growth of chemoresistant cells: a potential mechanism for superficial bladder cancer recurrence

Patients with superficial bladder cancer can be definitively cured by one single transurethral resection (TUR) with additional intravesical chemotherapy; however, up to 75 % of cases display frequent and multiple recurrences. One of the major causes of recurrence is that chemotherapeutic drugs used in intravesical regimens may induce chemoresistance. However, the mechanisms by which these chemoresistant cells develop into recurrent tumors remain unclear. Recent clinical evidence revealed that the expression of pro-angiogenic factor FGF2 was associated with early local relapse in patients with superficial bladder cancer. In this study, we conducted a preliminary investigation of the mechanisms of chemoresistant cells mediated bladder cancer recurrence, focusing on FGF2-initiated tumor cell-endothelial cell interaction on chemoresistant cancer cell growth. We found that the expression of FGF2 was increased in chemoresistant bladder cell lines and in bladder tissues after intravesical chemotherapy. Although chemoresistant bladder cells grow slower than parental cells, chemoresistant bladder cancer cells had stronger ability than parental cells to stimulate endothelial cell migration, growth, and tube formation by producing FGF2. Inversely, endothelial cells significantly promoted chemoresistant bladder cancer growth in vitro and in vivo. Thus, targeting chemotherapy-induced FGF2 upregulation may provide a promising approach to manage the recurrence of superficial bladder cancer.     

Intravesical chemotherapy of superficial bladder tumors

It has been reported that the intravesical instillation therapy had response rates ranging from 60 to 70% for bladder cancer and we could expect its significant efficacy, in terms of clinical benefits with quick response and lower medical cost, in patients of superficial and papillary peduncular tumors with multiple diseases and in diameter of maximum 1 cm. The intravesical instillation should be performed 2-3 times/week and within 2-3 weeks for the purpose to reach the clinical objectives. In order to enhance the efficacy of the intravesical instillation therapy, combined use of multiple anticancer agents or multidisciplinary treatments have been tried, in combination with systemic administration, radiotherapy, hyperthermia and hydro pressure therapy, which obtained remarkable clinical results. However, a comparative study has never been carried out among these treatments. It's a practical treatment that the intravesical instillation is given as an adjuvant therapy after TUR. In case of prophylactic purpose, the frequency and the period are still under discussion on the administration of the drugs. These is no clear idea yet which is optimal, a short period of administration for 1-2 weeks or a longer period for 2-5 years. Adriamycin and mitomycin-C have been commonly used for the intravesical instillation therapy of bladder cancer. BCG has recently had a good clinical response not only for therapeutic purpose of carcinoma in site but also for the prophylactic purpose with its intravesical instillation. Many studies indicated that the intravesical instillation therapy alone could not inhibit recurrence of bladder cancer under the current situation when the incidence of tumor and mechanism of recurrence are not yet clarified completely in epidemiological points of view. For improvement of treatment of bladder cancer, further fundamental studies must be developed and also a randomized trial is clinically needed, taking in consideration backgrounds of the patients, for evaluation of efficacy of bladder cancer treatment.     

Adjuvant intravesicular pharmacotherapy for superficial bladder cancer.

In 1990, bladder cancer, excluding carcinoma in situ, was estimated to contribute 49,000 cases of cancer. In men 75 years old or older, it became the fifth leading cause of cancer deaths. Of patients with bladder cancer, 75%-80% initially present with superficial bladder tumors. Treatment of these tumors has three objectives: 1) to eradicate existing disease, 2) to provide prophylaxis against tumor recurrence, and 3) to avoid deep invasion into the muscle layers of the bladder. Transurethral resection is the primary treatment to eradicate superficial bladder tumors, but 40%-80% of these tumors recur. Because of these high recurrence rates, adjuvant intravesicular pharmacotherapy with cytotoxic and immunomodulatory drugs has gained widespread use. The past two decades of clinical investigations in superficial bladder cancer have provided valuable information on the biology and treatment of the disease. Multivariate analyses have indicated that tumor grade and stage are the most important prognostic variables commonly available to the clinician to identify the patient at greatest risk of developing muscle-invasive or metastatic bladder cancer. These studies have also identified groups at low risk for tumor recurrence and invasive bladder cancer. Randomized trials have shown that recurrence rates are decreased by adjuvant intravesicular pharmacotherapy with a number of drugs: bacillus Calmette-Guérin vaccine (BCG), doxorubicin, ethoglucid (Epodyl), mitomycin-C, teniposide, and thiotepa. However, few studies indicate that adjuvant intravesicular pharmacotherapy can prevent progression to invasive bladder cancer in the high-risk patient with superficial bladder cancer. Additional clinical trials are needed to determine whether such therapy can prevent invasive and metastatic bladder cancer and improve disease-free survival in this group. In addition, the identification of tests (e.g., monoclonal antibody tests, chromosomal analyses, and tumor marker assays) that can help to identify high-risk patients is needed to better develop therapeutic strategies for superficial bladder cancer.     

丝裂霉素膀胱灌注预防浅表性膀胱肿瘤复发的远期疗效观察

目的 观察丝裂霉素预防浅表性膀胱肿瘤复发的远期疗效。方法 将１９８０年１月￣１９９１年１２月的８６例浅生膀胱肿瘤患者分为丝裂霉素组（手术＋丝裂霉素灌注）和对照组（单纯手术）,对两组的肿瘤术后复发率、病理分期和细胞分级进行对比观察。结果 丝霉素组７１例,对照组１５例,术后肿瘤复发率分别为４０．８％和６６．７％。丝裂霉素组在术后６月、１２月、２４月、３６月和６０月以上的无瘤率分别为８５．９％,７６．１     

膀胱癌癌旁组织的病理学及p53蛋白、bcl-2表达意义

 目的　探讨膀胱癌癌旁组织的病理学改变和p5 3、bcl 2基因的表达意义。方法　采用免疫组化SP法 ,对 5 8例行手术治疗的膀胱癌标本 ,分别进行 p5 3、bcl 2基因的检测。 结果　p5 3阳性表达在膀胱癌的不同病理分期及分级中具有显著性差异 (P <0 .0 1) ;bcl 2基因阳性表达在浅表性膀胱癌与浸润性膀胱癌具有差异 (P <0 .0 5 ) ,bcl 2基因阳性表达在不同病理分级中具有显著性差异 (P <0 .0 1)。结论　p5 3阳性表达、bcl 2阴性表达的膀胱癌具有恶性程度高、易复发的特点 ;癌旁组织恶变发生率 ,浸润性膀胱癌 5 6 .4 % ,浅表性膀胱癌 2 1.1% ,提示手术时尽可能保证足够的切除范围。     

Effect of 8-MHz radiofrequency-capacitive regional hyperthermia with strong superficial cooling for unresectable or recurrent colorectal cancer

A well-known disadvantage of a radiofrequency-capacitive device for deep-seated tumours is preferential heating of the subcutaneous fat tissue. The authors previously developed the hyperthermia with their own external cooling unit and achieved strong superficial cooling, and reported its usefulness for the reduction of the preferential heating. The purpose of the present study was to evaluate the effect of hyperthermia with strong superficial cooling on the treatment results for unresectable or recurrent colorectal cancers. From 1986 to 2002, 44 patients with primary unresectable or locally recurrent colorectal cancer treated with thermoradiotherapy were analysed retrospectively. The patients with obesity as a subcutaneous fat thickness more than 3?cm, a high age or other serious complications did not undergo therapy. The results were compared between 17 cases with strong superficial cooling treated after 1997 (Group A) and 27 cases without strong superficial cooling treated before 1996 (Group B). Significant differences in thermometry data of T_max, T_ave and T_min were noted between Groups A (45.3, 44.4 and 43.6°C, respectively) and B (42.9, 42.0 and 41.1°C, respectively) (p<0.01). Complete response plus partial response rates were better for Group A than for Group B (59 versus 26%, p?=?0.05). Multivariate analysis by logistic regression to evaluate the effects of certain factors on complete response plus partial response was strongly correlated with strong superficial cooling (p<0.05). The median survival times for overall survival were 24.3 months for Group A and 17.1 months for Group B (p<0.05). Eight-megahertz radiofrequency-capacitive regional hyperthermia with strong superficial cooling is potentially useful for improving treatment results in unresectable or recurrent colorectal cancers.     

Treated natural history of superficial bladder cancer.

BACKGROUND: The present study was conducted to examine the natural history of superficial bladder cancer. METHODS: One hundred and forty-four patients with superficial bladder cancer who had been treated with transurethral resection of bladder tumor (TURBt) alone were analyzed. RESULTS: The non-recurrence rate was 64.8% at 36 months and 61.2% at 60 months after TURBt. When the non-recurrence rate after TURBt was analyzed by background variables, the rate differed significantly between the solitary tumor group and the multiple tumor group. The tumor recurrence hazard curves for the entire population had one high peak before 500 days and another slight peak around 1500 days after TURBt. CONCLUSIONS: These results will provide basic information useful when evaluating new regimens of intravesical instillation therapy for prophylaxis of superficial bladder cancer after our complete TURBt in the Nara Uro-Oncology Research Group.     

A new antitumor drug with immunomodulating activity, ubenimex (bestatin)

Ubenimex (Bestatin) was discovered by Umezawa et al. in 1976 from the culture broth of Streptomyces olivoreticuli. Bestatin is a compound of low-molecular weight peptide and inhibits leucine aminopeptidase and aminopeptidase B which localized in cell membrane. Bestatin exhibited antitumor effect against murine syngeneic tumors including mouse colon 26 and C1498 leukemia, and also it was active against MNNG-induced rat tumor by oral administration. Combination treatment of mouse colon 26 with bestatin and mitomycin C, 5-FU or CDDP was effective for the life prolongation of the treated mice compared to mono-therapy alone. Bestatin was found to exhibit the antitumor effect through T lymphocyte stimulation, macrophage activation and bone marrow stem cell stimulation were also observed by bestatin treatment experimentally. Values of T cell subsets in cancer patients recovered to the normal levels by Bestatin treatment. Release of Interleukin-1 and -2 was enhanced by Bestatin treatment in vitro. In the phase I study, clinical optimal daily dose was estimated as 10-100 mg to give 2-3 times weekly or daily continuously. In the comparative clinical trials, Bestatin was found to be effective for the prolongation of survival time of the patients with acute non-lymphocytic leukemia after induction of complete remission in combination with maintenance chemotherapy. Minimal side effects were noted.     

Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma.

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 bladder cancer: prophylaxis of recurrence and progression]

Superficial bladder cancer has a good prognosis compared with invasive bladder cancer. However, recurrence of the tumor is frequent and tumor stage and/or grade progress at the time of recurrence in many cases. Intravesical chemotherapy has been employed as a prophylactic method after trans-urethral resection (TUR). Although intravesical chemotherapy has been proved to be effective in delaying the first recurrence of tumor after TUR, it cannot improve the ultimate prognosis of superficial bladder cancer. Many primary, solitary, non-invasive (Ta) and grade 1 tumors do not recur or progress in stage and grade. In these cases, prophylactic intravesical chemotherapy is not essential. Bacille Calmette-Guérin (BCG) should be considered superior overall, to any chemotherapeutic agents. Comparative studies will give information about the best clinical schedule for the treatment of superficial bladder cancer.     

Randomized study of single instillation of epirubicin for superficial bladder carcinoma: long-term clinical outcomes

PURPOSE: Intravesical instillation of epirubicin (EPI) is one of the most effective adjuvant therapies for nonmuscle-invasive bladder cancer postoperation. We evaluated the long-term efficacy of single dose intravesical epirubicin for superficial bladder carcinoma recurrence. METHODS: Between June 1997 and May 1998, a total of 47 patients with resectable superficial bladder carcinoma (Ta-1, Grade 1-2), primary or recurrent with no recurrence during last one year, were enrolled in this study. All patients were randomized into 3 study groups: Group A-single epirubicin (80 mg/40 mL of normal saline) was administered into the bladder within 6 hours postoperation; Group B-40 mg Epirubicin consecutively; Group C-40 mg mitomycin C, consecutively. In Group B and C, instillation were given every week for 6- 8 weeks and then every one month for 10 months. Patients were followed up at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months of treatment. The analyzed background factors were the therapeutic method, tumor recurrence, and side effects. RESULTS: Of the 47 patients, 43 (91.5 percent) were eligible and were followed up for 5 years postoperation. The disease free intervals of the three groups were found to have no significant differences (F = 10.28, p > 0.05). The recurrence rates were 35.7 percent (5/14), 33.3 percent (5/15), and 40 percent (6/15), respectively (chi(2)= 0.83, p > 0.05). Side effects of group A (13.6 percent) was lower than that of Group B or C (53.3 percent and 46.7 percent, respectively) significantly (chi(2) test, p < 0.01). CONCLUSIONS: These data indicate that single dose of epirubicin instillation postoperation can reduce the recurrence of superficial bladder carcinoma and has low side effects.     

2μm激光在经尿道膀胱肿瘤切除术中的应用

目的探讨2μm激光治疗膀胱肿瘤的手术方法和优势。方法采用RevoLix2μm激光手术系统治疗膀胱肿瘤137例,其中单发肿瘤109例,多发肿瘤28例,肿瘤直径2～35 mm,135例肿瘤病理为膀胱移行细胞癌,G1～G3,临床分期T1～T2。结果所有手术顺利完成,手术时间5～35min,术中出血量0～10 ml,均未出现膀胱穿孔、水中毒、尿外渗、术后大出血,并于24 h内即刻膀胱灌注化疗,并维持膀胱灌注化疗。术后尿管留置3～5 d,术后住医院3～5 d,术后随访3～31个月,无手术区复发。结论 2μm激光手术系统经尿道治疗T2期内膀胱癌安全有效。其与经尿道膀胱肿瘤电切术比较,在术中操作及避免并发症方面有一定优势。     

热疗联合顺铂与多西他赛化疗治疗晚期胃癌腹水的临床观察

为了探讨热疗联合化疗治疗晚期胃癌腹水的临床疗效,对9例伴有腹水的晚期胃癌患者,利用内生场局部热疗仪治疗腹部转移病灶,加温至41℃,持续1h,配合顺铂40 mg/m2腹腔给药,多西他赛30 mg/m2静脉滴入化疗,均每周1次,连续3周为1个周期.观察腹水疗效、腹部实体病灶缓解程度和热化疗后的不良反应.结果热化疗后9例患者中有3例腹水消退,6例腹水得到控制;腹部可测量病灶部分缓解4例,稳定2例;没有出现热化疗不良反应叠加.初步研究结果提示,热疗联合顺铂腹腔给药与多西他赛静脉滴入能够较好控制晚期胃癌腹水,并可获得较好的局部病灶缓解.     

浅表性膀胱癌二次经尿道电切的意义

目的:探讨对表浅性膀胱癌实施二次经尿道膀胱肿瘤电切术的指征和意义。方法:以确立的二次经尿道膀胱肿瘤电切术入选标准对126例表浅性膀胱癌患者实施手术,满足条件的81例患者中32例拒绝二次手术为A组,49例在术后4周行二次经尿道膀胱肿瘤电切术为B组,2组患者术后膀胱灌注相同。所有患者随访2年,比较2组间膀胱肿瘤进展率和复发率。结果:A组患者在术后2年随访中共有14例出现复发,分别为术后半年3例,1年内8例,1年至2年间6例。B组的16.3%（8/49）患者在第二次手术时发现肿瘤。2年随访期间复发8例,其中1年内3例,1年后5例,2组间在肿瘤复发上有统计学差异。结论:二次经尿道膀胱肿瘤电切术能降低非肌层浸润性膀胱癌患者的肿瘤复发;切除标本中有无肌层是明确手术切除彻底的标志。经尿道膀胱肿瘤电切术需要经验丰富的医师实施。