Hyperthermic Mitomycin C in Intermediate-risk Non-muscle-invasive Bladder Cancer: Results of the HIVEC-1 Trial.

BACKGROUND: Optimising therapeutic strategies of intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) is needed. OBJECTIVE: To compare recurrence-free survival (RFS) with adjuvant intravesical mitomycin C (MMC) at normothermia or hyperthermia using the COMBAT bladder recirculation system at 43 °C for 30 and 60 min. DESIGN, SETTING, AND PARTICIPANTS: A prospective open-label, phase 3 randomised controlled trial (HIVEC-1) accrued across 13 centres between 2014 and 2020 in Spain. After complete transurethral resection of the bladder and immediate postoperative MMC instillation, patients with IR-NMIBC were randomised (1:1:1) to four weekly followed by three monthly 40-mg MMC instillations at normothermia (control; n = 106), 43 °C for 30 min (n = 107), or 43 °C for 60 min (n = 106) were investigated. Therapeutic compliance was defined as four or more instillations. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was RFS at 24 mo in the intention-to-treat (ITT) and per-protocol (PP) populations. The secondary outcomes included progression-free survival at 24 mo, safety outcome measures, and changes in health-related quality of life. Log-rank, Fisher, χ2, and analysis of variance tests were used. RESULTS AND LIMITATIONS: The ITT 24-mo RFS was 77% for control, 82% for 43 °C-30 min, and 80% for 43 °C-60 min (p = 0.6). The PP 24-mo RFS was 77% for control, 83% for 43 °C-30 min, and 80% for 43 °C-60 min (p = 0.59). Six patients progressed to muscle-invasive disease in the ITT population (four in the control, 43 °C-30 min, and 43 °C-60 min groups each) and four in the PP population (all controls). Serious adverse events occurred in 26 patients (8.1%), and we were unable to demonstrate a difference between groups (p = 0.5). Adverse events, mainly dysuria and spasms, occurred in 124 patients (33% in control, 35% in 43 °C-30 min, and 48% in 43 °C-60 min; p = 0.05). The total International Prostate Symptom Score worsened by 1.2 ±â€¯7.3 points, similarly across groups (p = 0.29). The Functional Assessment of Cancer Therapy-Bladder domains and indexes showed no significant change. CONCLUSIONS: Four-month adjuvant hyperthermic MMC using the COMBAT system for 30 and 60 min in IR-NMIBC is well tolerated, but we did not find it to be superior to normothermic MMC at 24 mo. PATIENT SUMMARY: We were unable to demonstrate the effectiveness of hyperthermia using the COMBAT system in intermediate-risk non-muscle-invasive bladder cancer. Further evaluation of long-term recurrence and progression, and maintenance regimens appears mandatory.

Liver.

The liver's unique metabolism and relationship to the gastrointestinal tract make it an important target of the toxicity of drugs and xenobiotics. The developmental changes that occur in the liver's metabolic activity from birth to adolescence contribute to the varied sensitivity to toxins seen in the pediatric population. Hepatic drug metabolism, often with an imbalance between the generation of toxic metabolites and detoxification processes, can influence the degree of hepatotoxicity. The decreased capacity of the neonatal liver to metabolize, detoxify, and excrete xenobiotics explains the prolonged action of drugs such as phenobarbital, theophyline, and phenytoin. The reduced capacity of glucuronide conjugation in the neonate not only predisposes them to physiologic jaundice but also is probably responsible for the chloramphenicol-induced gray infant syndrome. Age-related sensitivity to drugs is attributable in part to differences in metabolic activity. For example, young children are more resistant to acetaminophen hepatotoxicity when compared with adults, whereas children are more susceptible to valproic acid-induced toxicity. The resistance to acetaminophen toxicity is attributable to biochemical differences in young children. In children, sulfation predominates over glucuronidation, leading to decreased formation of toxic intermediates. In addition, infants have a greater capacity to synthesize glutathione, thereby inactivating toxic metabolites of acetaminophen more effectively. Hepatic toxicity as a result of drugs and environmental toxins presents a wide spectrum of clinical disease. Hepatitis is the most common presentation, but every major type of liver pathology can occur. Most drug reactions are attributable to idiosyncratic hepatotoxins; therefore, liver injury occurs rarely. The diagnosis of toxin-induced liver disease requires a high index of suspicion and often entails the exclusion of other causes of liver disease in children. Drug or environmental xenobiotic-induced hepatotoxicity should be considered in the setting of identified exposure or when other causes of childhood liver disease are excluded. Children who take medications that are known to be hepatotoxic, such as anticonvulsants and antineoplastic drugs, need frequent monitoring for evidence of hepatic toxicity. The treatment is often nonspecific; the most important intervention is the prompt discontinuation of the drug or removal of the environmental toxin. A specific antidote is available only for acetaminophen intoxication. In cases of severe toxicity, the patient may develop liver failure. Liver transplantation may be necessary for patients whose liver failure does not resolve.