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Biomedical subjects

M Overgaard

Publications and source records attributed to M Overgaard.

At least 73 records · Page 4Linked to original sources
PubMed1988

Spontaneous radiation-induced rib fractures in breast cancer patients treated with postmastectomy irradiation. A clinical radiobiological analysis of the influence of fraction size and dose-response relationships on late bone damage.

The influence of fraction size on normal tissue damage was analysed in 231 patients treated with postmastectomy irradiation given either with a 12-fraction regimen (1978-1980) or with a 22-fraction regimen (1981). Chest radiographs taken 1-6 years after treatment were reviewed for spontaneous, radiation-induced rib fracture within the treated area. Patients treated with a large dose per fraction had significantly higher incidence of late bone damage (19%) than patients treated with a standard dose per fraction (6%) even though they had been treated with the aim to obtain equivalent biologic response according to the NSD formula. Furthermore, there was a clear dose-response relationship, especially in the 12-fraction regimen, where the total dose at the reference point varied over a wide range. Isoeffect doses could be estimated for the two different fractionation schedules. Using the linear quadratic model, alpha/beta ratios for late bone damage were estimated to be within the range of 1.8-2.8 Gy, i.e. similar to those reported for other late responding normal tissues.

Breast Neoplasms↗
PubMed1988

A Danish randomized trial comparing breast-preserving therapy with mastectomy in mammary carcinoma. Preliminary results.

The present study comprises 847 women operated upon for invasive breast carcinoma at 19 surgical departments and enrolled in protocol DBCG-82TM from January 1983 to November 1987. Among them 662 (78%) were allocated for breast-preserving therapy or mastectomy by randomization, while 185 patients (22%) did not accept randomization. Within the randomized group 6% could not be entered into adjuvant protocols, i.e. subsequent programmes of postoperative therapy and follow-up. This left 619 evaluable patients. In the non-randomized series 26% did not fulfil the demands for entrance into the adjuvant protocols, leaving 136 evaluable patients, 60 of whom had chosen a breast-preserving operation and 76 mastectomy. In the randomized series the patients in the two treatment arms were comparable in age, menopausal status, site of tumour, pathoanatomical diameter of the tumour, number of removed axillary lymph nodes, number of metastatic axillary lymph nodes, and distribution on adjuvant regimens. Ninety per cent of the patients in the randomized group accepted the method offered, whereas 10% declined and wanted the alternate form of operation. The median follow-up period was approximately 1.75 years. The cumulative recurrence rate in the randomized group was 13% and in the non-randomized group 7%. These results are preliminary. Life-table analyses have not so far demonstrated differences in recurrence-free survival either in the randomized or the non-randomized series.

Adult↗
PubMed1988

Adjuvant therapy of premenopausal and menopausal high-risk breast cancer patients. Present status of the Danish Breast Cancer Cooperative Group Trials 77-B and 82-B.

From September 1977 to November 1987 high-risk (i.e. with positive axillary lymph nodes, or tumor size greater than 5 cm or skin/facia invasion) premenopausal and menopausal breast cancer patients have been included in 2 randomized trials. In both trials the primary surgical treatment was total mastectomy with axillary sampling. In the first trial (DBCG 77-B) 1034 patients all received postoperative radiotherapy (RT) and were further randomized to 1) no systemic treatment (0), 2) cyclophosphamide (C), or 3) cyclophosphamide + methotrexate + 5-fluorouracil (CMF). The chemotherapy was given for 1 year. With a median observation time of 7 years the actuarial survival after 9 years is 50, 60 and 65% respectively. Retrospectively, the survival benefit was observed to be most pronounced in patients with tumor size less than or equal to 5 cm and with less than or equal to 3 positive lymph nodes. In the subsequent study initiated in 1982 (82-B) all patients received CMF for 9 months. Furthermore they were randomized to 1) RT, 2) no further treatment, or 3) tamoxifen (TAM) for 1 year. As of November 1, 1987, 1308 patients have been included. At 4 years and with a median observation time of 2 years the survival is similar in the 3 groups. In conclusion, in high-risk premenopausal and menopausal patients adjuvant chemotherapy combined with RT resulted in a 20-30% relative reduction in mortality at 9 years compared with RT alone. Preliminary analysis of adjuvant CMF + RT, compared with CMF alone or with CMF + TAM, shows after a median observation time of more than 2 years no significant survival differences.

Adult↗
PubMed1988

Adjuvant treatment of postmenopausal patients with high risk primary breast cancer. Results from the Danish adjuvant trials DBCG 77 C and DBCG 82 C.

The efficacy of adjuvant treatment with tamoxifen was evaluated in protocol DBCG 77 C. Postmenopausal high risk patients (tumor greater than 5 cm, positive axillary nodes, or invasion to skin/fascia) were randomized after total mastectomy and axillary sampling to postoperative radiotherapy (control) or to radiotherapy plus treatment with tamoxifen (TAM), 30 mg daily for 1 year. A total of 1,716 patients entered the study. At 8 years of follow-up, (7 years median time of observation), we observed a significant increase of recurrence-free survival for the TAM treated group and a reduction in mortality, which is significant for patients less than 70 years of age. Retrospectively, an increased recurrence-free survival in TAM treated patients was significant in the following subgroups: tumor less than 5 cm, positive lymph nodes, anaplasia grade II and estrogen receptor level greater than 100 fmol/mg cytosol protein. In the subsequent trial (DBCG 82 C), 1,347 postmenopausal patients less than 70 years were randomized to one of the following 3 regimens: radiotherapy + tamoxifen, 30 mg daily for 1 year (TAM), TAM alone, or TAM + CMF (CMF i.v. day 1 every 4 weeks x 9). The survival is similar in the 3 groups at 4 years (2 years median time of observation).

Aged↗
PubMed1988

Postmastectomy irradiation in high-risk breast cancer patients. Present status of the Danish Breast Cancer Cooperative Group trials.

All pre- and postmenopausal high-risk breast cancer patients in the protocols DBCG 77 of the Danish Breast Cancer Cooperative Group received postmastectomy irradiation before randomization to either adjuvant systemic therapy or no such treatment. The actuarial loco-regional recurrence rate at 9 years was 6-17%, with the lowest rate in patients who also received additional adjuvant chemotherapy or tamoxifen. In a subsequent study (DBCG 82) the role of postmastectomy irradiation together with systemic treatment was evaluated in high-risk patients. Pre- and menopausal patients were randomized to postmastectomy irradiation + CMF (cyclophosphamide, methotrexate, 5-fluorouracil), CMF alone or CMF + TAM (tamoxifen). Postmenopausal patients were randomized to postmastectomy irradiation + TAM, TAM or CMF + TAM. At 4 years the loco-regional recurrence rate was significantly lower in the irradiated patients (5-7% vs. 23-33%). Further, disease-free survival was significantly improved in both pre- and postmenopausal irradiated patients compared with those who had only systemic treatment. At present, there are no significant differences between survival in the treatment groups. Thus, adjuvant systemic treatment alone (chemotherapy and/or tamoxifen) did not prevent loco-regional recurrences in high-risk patients after mastectomy and axillary lymph node sampling. However, a longer observation time is necessary to evaluate the consequence of primary optimal loco-regional tumour control in high-risk breast cancer patients with respect to survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

The value of the NSD formula in equation of acute and late radiation complications in normal tissue following 2 and 5 fractions per week in breast cancer patients treated with postmastectomy irradiation.

In 1978-1980, inclusive, all breast cancer patients referred for postmastectomy irradiation were treated by 2 fractions per week (73 patients) but due to a high incidence of late complications this fractionation schedule was changed from early 1981 to 5 fractions per week (66 patients) with dose adjustment according to the nominal standard dose (NSD) concept. The dose aim in both regimens was 1345 ret minimum target dose. This allowed a comparison of acute and late complications in the two patient groups treated to the same NSD value, but with different fractionation. The patients have been analysed with respect to acute and late reaction in the skin, subcutaneous tissue, lung and bone, as well as related complications, such as arm oedema and impairment of shoulder movement. Except for the acute skin reactions, all other endpoints could not be adequately predicted by the NSD formula. Thus, telangiectasia greater than or equal to grade 1 and skin fibrosis greater than or equal to grade 2 were found to be 75% and 67% in patients treated with the 2-fraction scheme versus 39% and 5% in patients treated with the 5-fraction scheme. In the 2-fraction regimen, a higher frequency of impairment of shoulder movement and arm oedema was found compared to the 5-fraction regimen, 38% versus 11% and 44% versus 33%, respectively. The acute lung reaction as well as late lung reaction were significantly more pronounced in the 2-fraction regimen than in the 5-fraction regimen (pneumonitis greater than or equal to grade 2, 43% versus 23%, and lung fibrosis greater than or equal to grade 2, 32% versus 17%, in the photon fields, respectively). Further, radiation-induced osteonecrosis in the ribs was significantly more frequent in patients treated with large dose per fraction (19% versus 2%). The data clearly demonstrates the danger by using the NSD formula in equation of two different fractionation schedules. This formula as well as other mathematical models can only be used with caution within the limitations defined by the underlying clinical and experimental data on which they have been derived.

Breast Neoplasms↗
PubMed1987

Orgotein in radiation treatment of bladder cancer. A report on allergic reactions and lack of radioprotective effect.

The possible protective effect of orgotein (a superoxide dismutase) on radiation cystitis and proctitis was studied in patients with carcinoma of the urinary bladder. A double-blind study in 60 patients was planned but due to unacceptable side effects only 30 patients were included. Radiation treatment was given with curative intent at a dose of 63 Gy in 30 fractions. Orgotein was injected 15 min after each daily radiation treatment at a dose of 4 or 8 mg. No effect of orgotein on tumour radiation response or on the acute radiation reactions in the bladder and rectum was detected. Marked subcutaneous infiltration and redness was seen at the local injection site in 5 patients. No general symptoms were observed. Intradermal tests and antibody titration tests showed that the local reactions were due to allergic reactions to the drug itself. The lack of radioprotective effect and the high frequency of unacceptable side effects makes orgotein an unsuitable drug in clinical radiation therapy.

Actuarial Analysis↗
PubMed1986

Some factors of importance in the radiation treatment of malignant melanoma.

The results of radiotherapy in 204 lesions of malignant melanoma in 114 patients were analysed with regard to radiobiological parameters such as total dose, dose per fraction, treatment time, tumour volume and also by various fractionation models. Ninety-seven of 204 lesions showed a complete response (CR) which was persistent in 80. Neither total dose, treatment time nor various modifications of the nominal standard dose (NSD) concept showed any well-defined correlation with response. There was, however, a significant relationship between dose per fraction and response so that high doses per fraction yielded a significantly better response (24% CR for doses less than 4 Gy vs. 57% CR for doses greater than or equal to 4 Gy, p less than 0.001). The lack of influence of treatment time influence allowed an analysis of the data according to the linear-quadratic model yielding an alpha/beta ratio of 2.5 Gy. Using this ratio, an iso-effect for different fractionation schedules could be estimated by the extrapolated total dose (ETD). This was further improved when corrected for the other important parameter which was tumour volume. Thus, an iso-effect formular for malignant melanomas could be calculated as ETDvol = D X ((d + 2.5)/2.5) X M-0.33 where d is total dose and dose per fraction in Gy, respectively and M is mean diameter (cm). The 50% response for ETDvol was found to be 86 Gy. This formular seems to be currently the best way to determine an optimal radiation schedule for effective radiation treatment of malignant melanoma. Treatment of 45 patients with only local or regional disease showed 26 patients who achieved local tumour control with a 56% 3-year survival compared to no survivors among 19 patients in whom the disease could not be controlled locally. This indicated that proper attention should be given to the local treatment of recurrent melanoma since this has important implications for survival. Successful treatment of malignant melanoma may be possible when the special radiobiological features of the disease are taken into account.

Dose-Response Relationship, Radiation↗
PubMed1985

A randomized study comparing two high-dose per fraction radiation schedules in recurrent or metastatic malignant melanoma.

Thirty-five tumors in 14 patients with metastatic or recurrent malignant melanoma were randomized to high dose per fraction radiotherapy at either 9 Gy X 3 or 5 Gy X 8 twice weekly. Complete and persistent regression was found in 24/35 (69%) and partial response in 10/35 of the tumors. The overall response rate was 97%. No difference was observed between the two treatment regimens. Acute and late radiation damage to normal tissue was acceptable and of the same magnitude in both schedules.

Erythema↗
PubMed1984

A phase I clinical study of Nimorazole as a hypoxic radiosensitizer.

Nimorazole, a 5-Nitromidazole compound has been shown in animal studies to have similar radiosensitizing properties to misonidazole at clinically acceptable dose levels. The drug is well absorbed in humans after oral administration with peak plasma levels occurring around 90 min after ingestion (range 35-135 min) and a plasma half life between 2 and 4.8 hours. Total doses of Nimorazole up to 60 grams given in daily doses with conventional radiation therapy have demonstrated a significant lack of side effects, in particular no demonstrable neurotoxicity.

Adult↗
PubMed1984

Dose-response relationship for radiation therapy of recurrent, residual, and primarily inoperable colorectal cancer.

One hundred and thirteen patients with advanced locoregional recurrent (77), residual (18) or primarily inoperable (18) colorectal carcinoma were treated with radiotherapy. Eighty-five patients had locoregional disease only and 28 had both local disease and distant metastases. The treatment was given with varying dose levels (23-73 Gy) in daily fractions of approximately 2 Gy in 3-8 weeks. This dose variation allowed an evaluation of the dose-response relationship for radiation treatment of this tumour. A good subjective response was obtained in 63%. This effect showed no dose-response relationship except for doses greater than or equal to 56 Gy, where all patients received relief of symptoms. Eighty-two per cent of evaluable patients achieved an objective response (PR 53%, CR 29%). The frequency and duration of the complete responses showed a marked dose-response relationship. Thus, at doses greater than or equal to 56 Gy, a 2-year actuarial complete response rate of 40% was found compared with 7, 4 and 0% at doses of 46-55 Gy, 36-45 Gy and less than or equal to 35 Gy, respectively. The dose-response relationship for local control also influenced the survival rate, although a number of patients died from distant metastases even when local control was obtained. However, with regard to locoregional disease, the 2-year survival was 53% for patients with complete tumour regression but only 8% for patients without complete tumour regression.

Adult↗
PubMed1984

Small cell anaplastic carcinoma of the lung. The Aarhus experience 1976-1981.

Over a 6-year period 179 patients with small cell carcinoma of the lung (SCLC), 152 with limited disease, 25 with extensive disease, and 2 who were not staged, were treated with chest irradiation and combination chemotherapy with CCNU, adriamycin and vinblastine. For all patients the 2-year survival was 19.9 +/- 3 per cent, and the 5-year survival 11.9 +/- 3 per cent. No patients with extensive disease survived for 5 years. This type of treatment has curative potential for SCLC limited disease, which calls for further trials based on this approach.

Aged↗
PubMed1983

Studies of the pharmacokinetic properties of nimorazole.

The pharmacokinetics of the hypoxic radio-sensitizer nimorazole were studied in 19 individuals after single oral doses of between 0.5-3.5 g. HPLC measurements showed, after a rapid absorption, a linear relationship between peak plasma concentration and given dose. Mean elimination half life was 3.1 h. A tendency to a dose-dependent variation in the apparent volume of distribution, total body clearance and elimination half life suggest non-linear pharmacokinetics of nimorazole. Tumour concentrations measured in 5 patients gave tumour/plasma ratios between 0.8-1.3. No toxicity was observed. The results indicate that nimorazole may have potential as a clinically useful hypoxic radiosensitizer.

Adult↗
PubMed1982

A comparative investigation of nimorazole and misonidazole as hypoxic radiosensitizers in a C3H mammary carcinoma in vivo.

The hypoxic cell radiosensitizing properties of nimorazole have been investigated in a C3H mammary carcinoma transplanted to the feet of C3D2F1. The results have been compared with those obtained with misonidazole (MISO) in the same animal tumour system. For single-dose irradiation in air, nimorazole gives an enhancement ratio (ER) of approximately 1.4, independent of the dose of drug administered over the range 0.1-1.0 mg/g. MISO yields a similar ER at the 0.1 mg/g level but, unlike nimorazole, shows a steep dose-response curve with an ER of 2.2 when given in a concentration of 1.0 mg/g. No such dose-response relationship is seen with nimorazole despite the fact that tumour and plasma concentrations of the 2 drugs have an identical dose relationship. With irradiation given in 5 daily fractions, nimorazole and MISO at a dose of 0.3 mg/g per fraction both show an ER of approximately 1.3. The high drug doses used in single-fraction radiation experiments in animals bear little relation to those applicable to clinical practice since these would result in unacceptable toxicity. The results of the present studies are therefore of interest as nimorazole is potentially less toxic than MISO in humans but demonstrates similar radiosensitizing properties at clinically relevant dose levels.

Animals↗