Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. The management of deeply infiltrating (T3) bladder carcinoma: controlled trial of radical radiotherapy versus preoperative radiotherapy and radical cystectomy (first report). Evaluation of nurse-led follow up for patients undergoing pelvic radiotherapy. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Radical pelvic surgery versus radical surgery plus radiotherapy for stage Ib carcinoma of the cervix uteri. Preliminary results of a prospective randomized clinical study. Preoperative radiochemotherapy and radical surgery in comparison with radical surgery alone. A prospective, multicentric, randomized DOSAK study of advanced squamous cell carcinoma of the oral cavity and the oropharynx (a 3-year follow-up). Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective, randomized trial. Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience.
Despite aggressive local therapy, patients with locally advanced bladder cancer are at significant risk for metastases. We evaluated the ability of neoadjuvant chemotherapy to improve the outcome in patients with locally advanced bladder cancer who were treated with radical cystectomy.
                Patients were enrolled if they had muscle-invasive bladder cancer (stage T2 to T4a) and were to be treated with radical cystectomy. They were stratified according to age (less than 65 years vs. 65 years or older) and stage (superficial muscle invasion vs. more extensive disease) and were randomly assigned to radical cystectomy alone or three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy.
                We enrolled 317 patients over an 11-year period, 10 of whom were found to be ineligible; thus, 154 were assigned to receive surgery alone and 153 to receive combination therapy. According to an intention-to-treat analysis, the median survival among patients assigned to surgery alone was 46 months, as compared with 77 months among patients assigned to combination therapy (P=0.06 by a two-sided stratified log-rank test). In both groups, improved survival was associated with the absence of residual cancer in the cystectomy specimen. Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group (38 percent vs. 15 percent, P<0.001).
                As compared with radical cystectomy alone, the use of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy increases the likelihood of eliminating residual cancer in the cystectomy specimen and is associated with improved survival among patients with locally advanced bladder cancer.
                Copyright 2003 Massachusetts Medical Society Chemotherapy is widely used in patients with locally advanced bladder cancer but until now there has been no conclusive evidence that this therapy improves survival. The Nordic Cooperative Bladder Cancer Study Group conducted a randomized phase III study to assess the possible benefit of neoadjuvant chemotherapy in patients with bladder cancer undergoing radical cystectomy after short-term radiotherapy.
                Our trial included 325 patients with locally advanced stage T1 grade 3 or stages T2 to T4aNXM0 bladder cancer allocated randomly into a chemotherapy or no chemotherapy group (control). The chemotherapy schedule consisted of 2 cycles of 70 mg./m.2 cisplatin and 30 mg./m.2 doxorubicin with a 3-week interval between the cycles.
                After 5 years the overall survival rate was 59% in the chemotherapy group and 51% in the control group (p = 0.1). The corresponding cancer specific survival rate was 64 and 54%, respectively. In regard to treatment, no difference was observed for stages T1 and T2 disease, while there was a 15% difference in overall survival for patients with stages T3 to T4a disease (p = 0.03). In a multivariate analysis only chemotherapy and T category emerged as independent prognostic factors. The relative death risk for patients who received chemotherapy was 0.69 (95% confidence interval 0.49 to 0.98) compared to the control group after adjustment for the other tested factors.
                Neoadjuvant chemotherapy seems to improve long-term survival after cystectomy in patients with stages T3 to T4a bladder carcinoma, while no survival benefit was found for stages T1 to T2 disease. The preliminary results are presented of a multicentre, co-operative randomised trial, sponsored by the Institute of Urology, London, in which radical irradiation (6,000 rads in 6 weeks) is compared with preoperative irradiation (4,000 rads in 4 weeks) plus radical cystectomy for deeply infiltrating carcinoma of the bladder (Stage T3 or B2C). 189 of the 199 cases entered into the trial between 1966 and 1975 were eligible for study. The overall 3- and 5-year survival rates for combined treatment were 41% and 33%, respectively, compared with 28% and 21% for radical radiotherapy. The operative mortality was 7.8%. The difference between the two treatments in favour of the combined treatment has not yet reached the generally accepted level of significance (P less than 0.05), the p factors for the 3- and 5-year results being 0.064 and 0.077, respectively. Of patients receiving the protocol combined treatment, reduction in tumour stage was found in the surgical specimen in 47% of cases. The overall incidence of nodal metastases was 23% (against the usual figure of 40-50%), and in the presence of a good response of the primary tumour to irradiation, only 8%. The 3- and 5-year survival rates for the down-staged cases were 66% and 55%, respectively, compared with 29% and 22% for patients showing no stage reduction in the surgical specimen. The aim of our future studies is to find effective radiosensitising and cytotoxic agents with which to try and increase the incidence and degree of tumour response to pre-operative irradiation in the combined modality treatment of T3 bladder cancers. This study reports results from a randomised controlled trial of nurse-led care and was designed to determine whether nurse-led follow up improved patients morbidity and satisfaction with care in men treated with radical radiotherapy for prostate and bladder cancer. The aim was to compare outcomes in terms of toxicity, symptoms experienced, quality of life, satisfaction with care and health care costs, between those receiving nurse-led care and a group receiving standard care. The study population was of men prescribed radical radiotherapy (greater than 60 Gy). Participants completed self-assessment questionnaires for symptoms and quality of life within the first week of radiotherapy treatment, at week 3, 6 and 12 weeks from start of radiotherapy. Satisfaction with clinical care was also assessed at 12 weeks post-treatment. Observer-rated RTOG toxicity scores were recorded pre-treatment, weeks 1, 3, 6 and 12 weeks from start of radiotherapy. The results presented in this paper are on 115 of 132 (87%) of eligible men who agreed to enter the randomised trial. 6 men (4%) refused and 11 (8%) were missed for inclusion in the study. Data were analysed as a comparison at cross-sectional time points and as a general linear model using multiple regression. There was no significant difference in maximum symptom scores over the time of the trial between nurse-led follow-up care and conventional medical care. Differences were seen in scores in the initial self assessment of symptoms (week 1) that may have been as a result of early nursing intervention. Those men who had received nurse-led care were significantly more satisfied (P < 0.002) at 12 weeks and valued the continuity of the service provided. There were also significant (P < 0.001) cost benefits, with a 31% reduction in costs with nurse-led, compared to medically led care. Evidence from this study suggests that a specialist nurse is able to provide safe follow up for men undergoing radiotherapy. The intervention focused on coping with symptoms, and provided continuity of care and telephone support. Further work is required to improve the management of patients during and after radiotherapy. Local failure after prostatectomy can arise in patients with cancer extending beyond the capsule. We did a randomised controlled trial to compare radical prostatectomy followed by immediate external irradiation with prostatectomy alone for patients with positive surgical margin or pT3 prostate cancer.
                After undergoing radical retropubic prostatectomy, 503 patients were randomly assigned to a wait-and-see policy, and 502 to immediate postoperative radiotherapy (60 Gy conventional irradiation delivered over 6 weeks). Eligible patients had pN0M0 tumours and one or more pathological risk factors: capsule perforation, positive surgical margins, invasion of seminal vesicles. Our revised primary endpoint was biochemical progression-free survival. Analysis was by intention to treat.
                The median age was 65 years (IQR 61-69). After a median follow-up of 5 years, biochemical progression-free survival was significantly improved in the irradiated group (74.0%, 98% CI 68.7-79.3 vs 52.6%, 46.6-58.5; p<0.0001). Clinical progression-free survival was also significantly improved (p=0.0009). The cumulative rate of locoregional failure was significantly lower in the irradiated group (p<0.0001). Grade 2 or 3 late effects were significantly more frequent in the postoperative irradiation group (p=0.0005), but severe toxic toxicity (grade 3 or higher) were rare, with a 5-year rate of 2.6% in the wait-and-see group and 4.2% in the postoperative irradiation group (p=0.0726).
                Immediate external irradiation after radical prostatectomy improves biochemical progression-free survival and local control in patients with positive surgical margins or pT3 prostate cancer who are at high risk of progression. Further follow-up is needed to assess the effect on overall survival. In a preliminary report of a prospective controlled study treatment results and therapy morbidity of 60 patients with stage pT1bNoMo carcinoma of the uterine cervix treated by radical surgery only (Wertheim-Meigs) were compared with those of 60 patients treated by radical surgery followed by a postoperative external radiotherapy. The median duration of follow-up was 44 (24--72) months. Comparing the survival probability analyzed by life-table-method up to 18 months there was a significant better result for patients treated with surgery only. However, after that the study demonstrated comparable therapeutic results with the two therapeutic regimens. There was no difference of tumor size in patients who died after surgery alone and those who died after combined therapy. The therapy morbidity was slightly greater in patients treated by combined therapy. Especially lymphedemas of the leg developed more frequent in patients treated with combined surgery and radiotherapy. Preliminary analysis of the study does not demonstrate any beneficial effect of postoperative radiotherapy followed a radical hysterectomy with pelvic lymphonodectomy in cervical cancer stage pT1bNoMo, but optimal staging, radical surgery and carefully histological examination of the removed tissue are essential needs for this approach. A multicentric, randomized study of squamous cell carcinoma (SCC) of the oral cavity and the oropharynx has been undertaken by DOSAK. The results after radical surgery alone have been compared with the results of combined preoperative radiochemotherapy followed by radical surgery. Patients with primary (biopsy proven) SCC of the oral cavity or the oropharynx with tumor nodes metastasis (TNM) stages T2-4, N0-3, M0 were included in the study. A total of 141 patients were treated by radical surgery alone, whereas 127 patients were treated by radical surgery preceded by preoperative radiochemotherapy. The preoperative treatment consisted of conventionally fractioned irradiation on the primary and the regional lymph nodes with a total dose of 36 Gy (5 x 2 Gy per week) and low-dose cisplatin chemotherapy with 5 x 12.5 mg cisplatin per m2 of body surface during the first week of treatment. Radical surgery according to the DOSAK definitions (DOSAK, 1982) was performed after a delay of 10-14 days. During the follow-up period, 28.2% of all patients suffered from locoregional recurrence, and 27.2% of the patients died. The percentages were higher after radical surgery alone for locoregional recurrence (31% and 15.6%) and for death (28% and 18.6%). The life-table analysis showed improved survival rates of 4.5% after 1 year and 8.3% after 2 years in the group of patients treated with combined therapy. The demonstrated improvement appeared to be significant with the Gehan-Wilcoxon test as well as with the log rank test below a P value of 5%. A prospective, randomized clinical trial was conducted by the Northwest Rectal Cancer Group to study the effects of preoperative radiotherapy given one week before surgery in locally advanced (tethered or fixed) rectal carcinoma.
                A total of 284 patients were entered into the trial between 1982 and 1986; 141 were allocated to receive surgical treatment alone, and 143 were allocated to receive preoperative radiotherapy. A 10 x 10 x 10 cm volume in the posterior pelvis, centered on the tumor, was irradiated at a dose of 20 Gy, divided into four daily fractions of 5 Gy each.
                No differences were observed in any of the clinicopathologic variables in the two arms of the trial; there were no striking down-staging effects in the irradiated tumors. After a minimum follow-up period of 96 months, the overall and cancer-related mortality rates were similar in both arms of the study (P = 0.21 and P = 0.09, respectively). There was a highly significant reduction in local recurrences in the irradiated group (12.8 percent x-ray therapy vs. 36.5 percent surgery; P = 0.0001). The majority of local recurrences after preoperative radiotherapy occurred inside the radiotherapy field (10 cases; 7 percent), with only six cases (5 percent) outside the field. No significant difference was observed in the rates of distant metastasis between the two treatment groups (P = 0.73).
                Although there is no statistically significant survival benefit in the whole series, there is a survival benefit for the subset of patients considered by the surgeon to have undergone a curative operation. We recommend that this form of adjuvant therapy should be offered to all patients with locally advanced rectal cancer who are to undergo radical surgery. A total of 83 patients with nonorgan-confined bladder cancer with or without lymph node metastases (tumor stages pT3b, pT4a and/or pN1, pN2) was evaluated in November 1993 for relapse-free and overall survival. All patients underwent radical cystectomy between 1987 and 1991, 38 underwent adjuvant polychemotherapy with methotrexate, vinblastine and cisplatin plus doxorubicin (M-VAC) or epirubicin (M-VEC). Of the 83 patients 49 had entered a prospective randomized trial comparing adjuvant to no adjuvant treatment. The protocol was activated in May 1987. Patient recruitment was concluded in December 1990 because an interim analysis of the 49 randomized patients revealed a significant prognostic advantage in favor of the 26 patients randomized to the chemotherapy group compared to 23 in the control group (p = 0.0015, log-rank test for relapse-free survival curves). Preliminary data were published in 1992. Of the 26 patients randomized for adjuvant chemotherapy 18 were treated with M-VAC or M-VEC, 7 refused chemotherapy before or during cycle 1 and 1 received chemotherapy without cisplatin because of impaired renal function. The update of patient followup obtained in November 1993 continues to demonstrate a significant improvement in progression-free survival in favor of patients randomized for adjuvant chemotherapy (p = 0.0005). Followup of patients living free of disease ranged from 38 to 78 months. In a second analysis of actual treatment, the total collective of 83 patients treated from 1987 to 1991 was reviewed: 38 who had actually undergone adjuvant M-VAC/M-VEC (18 during the prospective trial and 20 in 1991 as the routinely recommended therapy) were compared with 45 without adjuvant M-VAC/M-VEC (7 refused to participate in the adjuvant trial, 8 randomized for but did not undergo adjuvant M-VAC/M-VEC, 23 belonged to the control group of the trial, and 7 underwent cystectomy in 1991 and remained without adjuvant treatment). This analysis again revealed a significant prognostic advantage in favor of the patients treated with adjuvant M-VAC/M-VEC. We conclude that adjuvant chemotherapy with M-VAC/M-VEC leads to a significant prolongation of relapse-free survival and to an improvement of the definitive cure rates after radical cystectomy for locally advanced transitional cell carcinoma of the bladder.
The analysis of this review suggests that there is an overall survival benefit with radical surgery compared to radical radiotherapy in patients with muscle-invasive bladder cancer. However, it must be considered that only three trials were included for analysis, the patients numbers were small and that many patients did not receive the treatment they were randomised to. It must also be noted that many improvements in both radiotherapy and surgery have taken place since the initiation of these trials.