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Acute and late morbidity in the treatment of advanced bladder carcinoma with accelerated radiotherapy, carbogen, and nicotinamide
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
2005 (English)In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 103, no 11, 2287-2297 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Accelerated radiotherapy combined with carbogen and nicotinamide (ARCON) to overcome tumor hypoxia and cell proliferation achieved high tumor control and survival in Phase II studies of patients with advanced head and neck and bladder carcinomas. Thus, morbidity and treatment outcomes from the latter study were analyzed to evaluate the therapeutic potential of ARCON. METHODS: Acute and late morbidity was assessed in 105 patients with high-grade superficial or muscle-invasive bladder carcinoma who were given accelerated radiotherapy (50-55 grays in 4 weeks) with carbogen alone or with ARCON. Urinary dysfunction was scored based on daytime frequency, nocturia, incontinence, dysuria, hematuria, and urgency. Bowel morbidity was based on stool frequency and consistency, rectal discharge, blood loss, and medication. Endpoints for treatment outcome were overall survival, disease-free survival, and locoregional control. RESULTS: Nearly all patients experienced reduced ability to retain urine beyond 2 hours, although 20-30% had almost normal function at night. Incidence of acute moderate or worse dysuria was 41% with ARCON and 56% with carbogen; 96% and 76% of patients, respectively, had bowel frequencies > or = 3 times per day. By 10-12 weeks from the start of radiotherapy, acute reactions returned to baseline levels. At 3 years, the daytime frequency < or = 2 times per hour was approximately 75% in both arms. Incidence of severe hematuria (< or = 25%) and urinary urgency (< or = 16%) was much lower. No more than 6% of patients had severe bowel morbidity. With most assays, the differences between schedules were not significant either for acute or late morbidity. Local tumor control and survival rates at 3 years were 53% and 43%, respectively, for ARCON, similar to the rates for carbogen alone. CONCLUSIONS: Historical comparisons suggested no overt increase in normal tissue radiosensitivity when adding carbogen and nicotinamide. Although, for some endpoints, the incidence of late sequelae was higher than expected, overall morbidity was no worse than reported by others. The data indicated that ARCON could achieve a therapeutic gain in patients with advanced bladder carcinoma. A Phase III, randomized, multicenter trial is underway currently in the United Kingdom to evaluate these findings.

Place, publisher, year, edition, pages
2005. Vol. 103, no 11, 2287-2297 p.
Keyword [en]
Bladder carcinoma, carbogen, nicotinamide, acute morbidity, late morbidity
National Category
Medical and Health Sciences
URN: urn:nbn:se:umu:diva-14419DOI: 10.1002/cncr.21048PubMedID: 15834926OAI: diva2:154090
Available from: 2006-11-09 Created: 2006-11-09 Last updated: 2010-08-11Bibliographically approved
In thesis
1. ARCON in experimental and clinical radiotherapy
Open this publication in new window or tab >>ARCON in experimental and clinical radiotherapy
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

xHypoxia and repopulation of tumour clonogens are two important determinants of treatment outcome in radiotherapy. In general clinical evidence indicates that loco-regional control may be reduced with long overall treatment times and for tumours with low pre-treatment levels of oxygen. Experimental studies with normobaric carbogen and oxygen showed a two-fold enhancement of the efficacy of radiation in a mouse tumour model when combining oxygen with treatment acceleration. It was then demonstrated that substituting carbogen for oxygen and adding high-dose nicotinamide (NAM) further increased the effect. These findings became the basis for a multi-factorial approach designed to overcome the radioprotective effect of tumour repopulation and that of perfusion–limited and diffusion–limited hypoxia. The strategy, named ARCON, combines Accelerated Radiotherapy with CarbOgen and Nicotinamide.

Experimental evaluation of ARCON

The therapeutic potential of carbogen combined with NAM (CON) focusing on treatment schedules that use clinically relevant radiation and drug dose levels was evaluated in tumour and normal tissue animal models. Some of the conditions under which ARCON gives the largest degree of tumour radiosensitization and therapeutic benefit were identified. Specifically, NAM-dose level, pharmacokinetics and scheduling, and the effect of NAM on repair processes in vivo were also investigated. The results showed that in conventional and accelerated radiotherapy, carbogen and CON are effective and relatively non-toxic tumour sensitizers. They also demonstrated that tumour sensitization with CON was independent of time of NAM administration but that it was drug dose dependent. Some degree of normal tissue sensitization was observed but even relative to mouse skin a significant therapeutic gain was achieved. The mechanism of action for NAM sensitization originally proposed was that of repair inhibition. In the in vivo mouse models tested, namely skin and kidney, NAM did not alter the rate nor the magnitude of repair of radiation induced damage.

Clinical evaluation of ARCON

In the early 90s, various centres, particularly in the UK, Sweden, Holland and Switzerland, undertook clinical trials of ARCON. The protocols were designed based on detailed considerations of the rodent and human radiation and pharmacokinetic studies. This document also discusses the findings of a phase II non-randomized trial in advanced bladder cancer of accelerated radiotherapy combined with carbogen alone and ARCON. The aim of the study was to establish the feasibility of administering carbogen and NAM to patients and to determine the extent of early and late normal tissue damage. Historical comparisons suggested no overt increase in normal tissue radiosensitivity and the data indicate that ARCON could achieve a therapeutic gain in advanced bladder cancer.

49 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 872
Oncology, ARCON, tumours, normal tissues, radiosensitization, carbogen, nicotinamide, repair inhibition, therapeutic gain, rodents, humans, Onkologi
National Category
Cancer and Oncology
Research subject
urn:nbn:se:umu:diva-207 (URN)91-7305-582-4 (ISBN)
Public defence
2004-04-28, Sal 244, 7, Norrlands universitetssjukhus, Umeå, 09:00
Available from: 2004-03-11 Created: 2004-03-11 Last updated: 2010-08-11Bibliographically approved

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