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ARCON in experimental and clinical radiotherapy
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
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.

Place, publisher, year, edition, pages
2004. , 49 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 872
Keyword [en]
Oncology, ARCON, tumours, normal tissues, radiosensitization, carbogen, nicotinamide, repair inhibition, therapeutic gain, rodents, humans
Keyword [sv]
Onkologi
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:umu:diva-207ISBN: 91-7305-582-4 (print)OAI: oai:DiVA.org:umu-207DiVA: diva2:142647
Public defence
2004-04-28, Sal 244, 7, Norrlands universitetssjukhus, Umeå, 09:00
Opponent
Supervisors
Available from: 2004-03-11 Created: 2004-03-11 Last updated: 2010-08-11Bibliographically approved
List of papers
1. Carbogen and nicotinamide as radiosensitisers in a murine mammary carcinoma using conventional and accelerated radiotherapy
Open this publication in new window or tab >>Carbogen and nicotinamide as radiosensitisers in a murine mammary carcinoma using conventional and accelerated radiotherapy
1996 (English)In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 34, no 2, 357-365 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To compare the radiosensitivity of mouse tumors treated in air with conventional and accelerated radiotherapy with that of tumors treated in carbogen alone or carbogen combined with nicotinamide. METHODS AND MATERIALS: CaNT mammary tumors were irradiated with either 30 x-ray fractions in 6 weeks or 40 fractions in 26 days in air, carbogen alone, or carbogen combined with 120 mg/kg of nicotinamide (NAM), the latter given intraperitonealy 30 min before each fraction. The response to treatment was assessed using local control, weight loss, and metastasis-free survival. RESULTS: Both carbogen and carbogen plus nicotinamide significantly increased tumor radiosensitivity; enhancement ratios (ERs) in the 6-week regimen were similar to those seen in the accelerated schedule. The majority of the effect was achieved by carbogen alone but the addition of NAM further enhanced tumor radiosensitization (ERs of 1.5 and 1.4 for carbogen in the conventional and accelerated schedule, respectively, were significantly lower than ERs of 1.7 and 1.6 obtained with carbogen plus nicotinamide; p < or = 0.005). Treatment protraction significantly increased radioresistance, especially when tumors were treated under air. An extra 1.5 Gy per day was required in air to counterbalance proliferation; in carbogen alone and carbogen plus nicotinamide a dose loss of 0.9 and 0.6 Gy per day was observed, respectively. Compared with treatments in air alone delivered in 6 weeks, acceleration of treatment combined with carbogen and nicotinamide gave the greatest increase in tumor radiosensitization (ER = 1.9). No toxic side effects and no detrimental changes in body weight were encountered when the sensitizers were administered 30 times (one fraction per day) or 40 times (two fractions per day). In both regimens, the incidence of metastases in mice treated with carbogen or carbogen plus nicotinamide was similar to that seen in animals treated in air. There was, however, a nonsignificant trend of a higher proportion of mice with metastasis in the accelerated schedule compared with the 6-week schedule. CONCLUSIONS: In both conventional and accelerated experimental radiotherapy, carbogen alone or combined with a small clinically relevant dose of NAM were well tolerated, achieved large and significant increases in radiosensitization, and did not affect the incidence of metastases. The sparing of damage, resulting from extending the overall treatment time, was less when the sensitizers were administered than when irradiations were performed in air. The study suggests that clinical radiotherapy regimens, which aim to reduce hypoxic and/or tumor clonogen proliferation, would benefit from the use of carbogen, especially if the gas is combined with nicotinamide and treatment acceleration.

Keyword
Acceleration, Fractionation, Radiotherapy, Tumors, Carbogen, Nicotinamide, ARCON, Metastasis, Overall time, Rodents
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-3774 (URN)10.1016/0360-3016(95)02087-X (DOI)8567336 (PubMedID)
Available from: 2004-03-11 Created: 2004-03-11 Last updated: 2017-12-14Bibliographically approved
2. Is sensitization with nicotinamide and carbogen dependent on nicotinamide concentration at the time of irradiation?
Open this publication in new window or tab >>Is sensitization with nicotinamide and carbogen dependent on nicotinamide concentration at the time of irradiation?
2004 (English)In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 80, no 7, 499-506 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To determine whether tumour radiosensitization and the therapeutic benefit of administering carbogen with nicotinamide depend upon irradiating at the time of peak drug concentration. MATERIALS AND METHODS: Local tumour control of CaNT tumours in CBA mice and acute skin reactions in albino WHT mice were assessed after treatment with 10 X-ray fractions in air, carbogen alone or combined with 0.1, 0.2 or 0.5 mg g(-1) nicotinamide, injected 15, 30 or 60 min before irradiation. Plasma and tumour drug pharmacokinetics were performed. RESULTS: Nicotinamide was rapidly taken up into tumours; a six- and threefold higher concentration was obtained with 0.5 mg g(-1) compared with 0.1 and 0.2 mg g(-1), respectively. Tumour, but not skin, radiosensitization increased as the dose of nicotinamide increased (p = 0.03), but at each dose level there was no significant difference in radiosensitivity when irradiations were done at or after the time of peak concentration. An almost eightfold increase in plasma levels increased tumour enhancement ratios from 1.74 to 1.92 (p < 0.0001). In tumours all schedules gave significant enhancement relative to carbogen alone (p < or = 0.04). CONCLUSIONS: Tumour and skin radiosensitivity was independent of time of nicotinamide administration. Higher drug concentrations were not mirrored by proportionally higher enhancement ratios. Lower plasma levels than previously suggested significantly enhanced tumour radiosensitivity relative to carbogen alone. The clinical implications of these findings are discussed.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-15542 (URN)10.1080/09553000410001724199 (DOI)15360088 (PubMedID)
Available from: 2006-11-13 Created: 2006-11-13 Last updated: 2017-12-14Bibliographically approved
3. Radiosensitisation in normal tissues with oxygen, carbogen and nicotinamide: therapeutic gain comparisons for fractionated X-ray schedules
Open this publication in new window or tab >>Radiosensitisation in normal tissues with oxygen, carbogen and nicotinamide: therapeutic gain comparisons for fractionated X-ray schedules
Show others...
1996 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 39, no 1, 53-64 p.Article in journal (Refereed) Published
Abstract [en]

METHODS: Radiosensitisation with oxygen, carbogen or nicotinamide alone and oxygen or carbogen combined with nicotinamide was compared in early and late responding normal tissues in rodents. X-ray treatments were delivered as single doses or fractionated schedules of 2 fractions in 1 day, 2, 12 and 36 fractions in an overall time of 12 days and 10 fractions in 5 or 12 days. Acute skin reactions, survival of intestinal crypts, breathing rate, reduction in the packed red-cell volume and clearance of 51Cr-EDTA were used as assays of epidermal, gut, lung and renal damage. RESULTS: Relative to air-breathing mice, carbogen or oxygen produced a small, and not always significant, increase in sensitivity (enhancement ratios < or = 1.15) in gut, lung and kidneys; however, in skin a dose enhancement of 1.2-1.3 was observed. The effect of nicotinamide in air, carbogen or oxygen was studied only in lung and gut. The drug produced variable but generally significant increases in radiosensitisation ( < or = 1.26) in all three gases. Relative to treatments in air, enhancement ratios for nicotinamide alone were usually slightly higher than those observed when either carbogen or oxygen were administered without the drug. With all three modifiers (i.e. oxygen, carbogen, nicotinamide alone or for the drug-gas combinations) there was no significant change in the enhancement ratios observed as the number of radiation dose fractions was varied. CONCLUSIONS: Comparisons with fractionated X-ray studies done previously in rodent tumours indicate that a therapeutic benefit, relative to lung, gut and renal damage, would be observed with oxygen or carbogen alone but not with nicotinamide alone. The greatest gain would be achieved with the combination of carbogen and nicotinamide, with which a benefit was observed even relative to epidermal damage. These results indicate that some decrease in normal tissue tolerance could be observed when using these modifiers in clinical radiotherapy and, although small, the appropriate dose reductions should be considered; caution should be exercised especially when carbogen and nicotinamide are used in conjunction with the more radical accelerated schedules.

Keyword
Oxygen, Carbogen, Nicotinamide, ARCON, Skin, Lung, Gut, Kidney, Fractionation, Therapeutic benefit
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-3776 (URN)10.1016/0167-8140(95)01678-3 (DOI)8735494 (PubMedID)
Available from: 2004-03-11 Created: 2004-03-11 Last updated: 2017-12-14Bibliographically approved
4. Nicotinamide as a repair inhibitor in vivo: single and fractionated X-ray dose studies in mouse skin and kidneys
Open this publication in new window or tab >>Nicotinamide as a repair inhibitor in vivo: single and fractionated X-ray dose studies in mouse skin and kidneys
Show others...
1996 (English)In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 145, no 4, 419-431 p.Article in journal (Refereed) Published
Abstract [en]

Inhibitors of adenosine diphosphoribosyl transferase, like nicotinamide, 3-aminobenzamide and other analogues, can inhibit repair of radiation-induced sublethal and/or potentially lethal damage in some in vitro systems. Therefore, we have tested the effect of nicotinamide on repair parameters in vivo in two rodent normal tissues. In skin, the sensitivity to dose fractionation (1, 2, 5 or 10 X-ray fractions in 5 days) was monitored by defining the alpha/beta ratio in the presence or absence of nicotinamide (0.5 mg g-1) in air or carbogen. Pre- and postirradiation sensitization were investigated using an X-ray schedule of 5 fractions/5 days in carbogen alone or combined with nicotinamide given 1 h before, immediately after or 8 h after irradiation. Also, changes in the steepness of the underlying X-ray survival curve for the target skin clonogens, reflected by a change in the alpha/beta ratio, were investigated using the neutron top-up design. Underlying survival curves for oxygen +/- nicotinamide were obtained over the X-ray dose range 2.5 to 25 Gy, by administering single X-ray doses and following these with single top-up doses of d(4)-Be neutrons. Finally, in mouse kidney, recovery half-times (t1/2) were obtained by determining the time-dependent disappearance of X-ray damage using a split-dose design of two 6-Gy fractions separated by an interval which varied from 0 to 48 h and followed by two top-up doses from a neutron beam. No increase in alpha/beta for epidermal damage was seen with nicotinamide alone and, although sensitization was observed when the drug was given 1 h before irradiation, no postirradiation sensitization was detected. In kidney, there was no significant difference in the proportion of total repairable damage or in the half-life of recovery between treatments given with or without nicotinamide. Therefore, no decrease in normal tissue tolerance should be observed with the use of nicotinamide in clinical radiotherapy resulting either from reduced sparing with dose fractionation or from an increase in residual damage when shortening the interfraction interval. Finally, unless repair of radiation damage in normal tissues in vivo differs markedly from that of tumors, it is unlikely that the large sensitization seen in rodent tumors at 1.5 to 2 Gy per fraction, with carbogen and nicotinamide, can be attributed to nicotinamide acting as a repair inhibitor.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-3777 (URN)8600502 (PubMedID)
Available from: 2004-03-11 Created: 2004-03-11 Last updated: 2017-12-14Bibliographically approved
5. Acute and late morbidity in the treatment of advanced bladder carcinoma with accelerated radiotherapy, carbogen, and nicotinamide
Open this publication in new window or tab >>Acute and late morbidity in the treatment of advanced bladder carcinoma with accelerated radiotherapy, carbogen, and nicotinamide
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.

Keyword
Bladder carcinoma, carbogen, nicotinamide, acute morbidity, late morbidity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-14419 (URN)10.1002/cncr.21048 (DOI)15834926 (PubMedID)
Available from: 2006-11-09 Created: 2006-11-09 Last updated: 2017-12-14Bibliographically approved

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