The use of hypothermia in intra-arterial chemotherapy for head and neck cancer.
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Sixty-four patients with multiple, superficial papillary bladder tumours which had ceased to be controlled by endoscopic resection and diathermy were treated before July 1972 with intravesical Epodyl instillations. Of these, 19 had developed no further recurrences; 20 patients were free of tumour to one year, but later developed recurrences. Twenty-four patients were never entirely free of tumour after starting Epodyl and one patient became free of recurrences 2 years after starting Epodyl. Only the patients whose histology showed no invasion of the lamina propria responded to treatment. The overall 5-year survival rate was 66%, with a disease-free interval of 61% at one year and 25% at 5 years. Failure to clear the bladder of tumour after 12 months' treatment, or worsening of biopsy stage from PIS to Pla or Plb while on treatment, were associated with a high risk of dying of invasive tumour and in future should be used as immediate indications for radical treatment.
Of 299 patients who presented with superficial bladder cancer (Ta, T1), 60 were treated by intravesical chemotherapy (Epodyl, methotrexate or mitomycin C). The rate of tumour progression to muscle invasion or metastases was identical for each intravesical regime. There was no evidence that mitomycin C promoted tumour progression. Carcinoma in situ in non-tumour-bearing urothelium was the most significant predictive factor for progression to muscle invasion or metastases.
The records of 111 patients with multiple superficial grade 1-2 transitional cell tumours of the bladder treated with intravesical Epodyl and followed up for a mean period of 6.4 years were retrospectively analysed. The study showed that 65% of patients responded completely after 12 weekly instillations and 46% of these remained continuously free of disease for 5 years. An initial complete response to therapy and lower pathological grade seemed to indicate a long-term successful response to treatment. In patients who failed to respond by 1 year, further therapy was of no benefit. Clearance of bladder disease by 1 year carried a 14% risk of subsequent tumour invasion by 5 years. This risk increased to 75% in those who failed to respond by 1 year.
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Management of the superficial bladder cancer patient consists of two complementary but separate therapeutic goals: treatment of the existing tumor(s) and prevention of tumor recurrence. At present, the stage, grade, and multicentricity are the major determinants in the natural and therapeutic history of the disease. Although intravesical instillation of chemotherapeutic agents has been used for greater than 20 years, neither its exact role nor the optimal dose or schedule of administration have been established. To date, no dramatic differences in efficacy between the agents commonly used for intravesical chemotherapy, either as definitive therapy or prophylaxis, have been appreciated. These agents do appear to lower the recurrence rate as well as extend the disease-free interval. Since the most thorough experience is with thiotepa, it is the drug against which other agents should be compared in terms of both efficacy and toxicologic evaluation. Different administration schedules and methodologies need further study, such as the utility of continuous bladder irrigation, the use of sequential chemotherapeutic agents to gain cell synchronization, and the use of multiple drug regimens. Because there are multiple factors that influence the occurrence and recurrence of bladder cancer, combined modality therapy deserves testing. Modes of therapy that could be used together because they act through different mechanisms are intravesical chemotherapy, radioactive needle implants, carcinogen modifiers such as pyridoxine, chemoprotective agents such as retinoic acid, and immune stimulants such as BCG. These studies should be performed in a randomized prospective controlled fashion, which may require cooperative multi-institutional involvement to accrue adequate numbers of patients. At this time there are a number of important questions that remain to be answered concerning the treatment of superficial bladder cancer: (1) does this mode of therapy affect overall survival, (2) does prophylactic intravesical chemotherapy alter the incidence of subsequent muscle invasive disease, (3) does intravesical chemotherapy alter the sites, incidence, or responsiveness to systemic chemotherapy of subsequent metastatic disease, and (4) and what is the optimal timing and duration of prophylactic therapy from a cost-effectiveness standpoint?
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Multiple, non-invasive bladder papillomas were treated with intravesical instillation of Epodyl in 44 patients. Irritative cystitis occurred in 16 per cent of the series, and in these cases Epodyl treatment had to be stopped. Total or partial disappearance of the papillomas was seen after 16 months of treatment in 43% of the total series. This was the minimum success rate, since all the patients who left the study were counted as failures. When the treatment could be carried through, total or partial disappearance of papillomas occurred in 19 of 29 patients (66%). Epodyl has a place in the treatment of vesical papillomas when other methods have failed.
Over a 5-year period 38 patients were treated at Rigshospitalet with intravesical instillation of Epodyl for multiple, non-invasive bladder tumours. The results were significantly inferior (p less than 0.00025) to those reported from other hospitals, though the composition of the case series was comparable. Analysis of procedure at Rigshospitalet revealed that when Epodyl was mixed with water in aluminium foil cups, which was standard practice at the outpatient department, the concentration was halved in 5 minutes. Ineffective treatment thus had been unwittingly given. The results, however, do not warrant rejection of Epodyl treatment; they may instead constitute direct evidence in it favour.
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The management of CIS of the bladder consists of two complementary but separate therapeutic goals: treatment of existing disease and the prevention of recurrence. At present the biological behavior and prognosis of CIS remains to be completely defined. To date, the majority of experience with the medical management of CIS of the bladder is with chemotherapeutic agent doxorubicin and the immunotherapeutic agent BCG. Other agents such as mitomycin and interferon appear promising. The efficacy of these drugs will have to be evaluated in prospective randomized trials. At that time a number of questions should be answered concerning the treatment of CIS of the bladder: what is the effect of these agents on morbidity and survival, what is the optimal dose, schedule, and duration of therapy for these drugs, and will the biology of the disease, e.g. extravesical recurrences mandate systemic therapy?
This investigation compares the short and long-term administration of intravesical Epodyl (etoglucid), following transurethral bladder tumor resection. This chemoprophylactic agent was used specifically in the treatment of bladder tumors that displayed different associated tumor risk factors: solitary versus multiple tumors, grade(s) I-III, primary versus recurrent tumors, and the presence of associated dysplasia. Within this study, 114 patients with carcinoma of the bladder underwent primary transurethral resection (TUR), followed in 10 days by short-term intravesical therapy (STIT) or long-term intravesical therapy (LTIT). Short-term intravesical therapy was administered to 56 patients. The therapy consisted of a 1% solution of Epodyl, which was given once per week for 6 weeks. Long-term intravesical therapy was given to 58 patients. This consisted of the short-term intravesical therapy protocol, followed by an additional dose once a month during an observation period of 2 years. The follow-up in both groups was for a minimum of 2 years. When the total number of recurrences in patients receiving (STIT) or (LTIT) was compared, no marked differences were noted (39% vs 38%). However, there was a difference when the individual tumor risk features were compared, e.g. for solitary tumors, the recurrence rate was 67% within the (STIT) group and 43% within the (LTIT). These results demonstrate that the decision of whether superficial bladder carcinomas are to be treated with short- or long-term Epodyl should be based on tumor-associated risk factors. Furthermore, if multiple tumor risk factors are present, maximal therapy is require; in the absence of risk factors TUR alone may be sufficient.