Why actuarial estimates should be used in reporting late normal-tissue effects of cancer treatment ... now!
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Actuarial Analysis↗
Biomedical subjects
J Overgaard
Publications and source records attributed to J Overgaard.
Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology.
The value of hyperthermia as an adjuvant to radiotherapy in patients with malignant melanoma was studied in a European multicentre trial. 134 metastatic or recurrent lesions of malignant melanoma in 70 patients were randomly assigned to receive radiotherapy (three fractions of 8 Gy or 9 Gy in 8 days) alone or followed by hyperthermia (43 degrees C for 60 min). Overall, the 2-year actuarial local tumour control was 37 (SE 5)%. Univariate analysis showed a beneficial effect of hyperthermia (radiation alone 28% vs combined treatment 46%, p = 0.008) and radiation dose (24 Gy 25% vs 27 Gy 56%, p = 0.02), but no effect of tumour size (< or = 4 cm 42% vs > 4 cm 29%, p = 0.21). Cox multivariate regression analysis showed the most important prognostic variables to be hyperthermia (odds ratio for 2-year local control 1.73 [95% CI 1.07-2.78], p = 0.023), tumour size (0.91 [0.85-0.99], p = 0.05), and radiation dose (1.17 [1.01-1.36], p = 0.05). Addition of heat did not significantly increase acute or late radiation reactions. Heating was well tolerated, but because of difficulties with equipment only 14% of treatments achieved the protocol objective. The overall 5-year survival rate was 19%, but 38% of the patients for whom all known disease was controlled survived 5 years. Adjuvant hyperthermia significantly improved local tumour control when applied in association with radiation in treatment of malignant melanoma. Successful local treatment of patients with a single or a few metastatic malignant melanoma lesions has significant curative potential.
Adult↗
Renal damage after total body irradiation in a mouse model for bone marrow transplantation: effect of radiation dose rate.
Late renal damage after total body irradiation (TBI) and bone marrow transplantation (BMT) is a recently recognised morbidity. We have tested the effect of single fraction TBI given at two different dose rates on late kidney damage in a mouse model. TBI was given at either high dose rate (HDR; 0.71 Gy/min) or low dose rate (LDR; 0.08 Gy/min). Transplantation with syngeneic marrow cells was done 4-6 h after TBI. Kidney damage was tested using 51CrEDTA residual activity, blood urea nitrogen (BUN) and percentage haematocrit (Hct). TBI alone given at HDR or LDR caused progressive renal damage with no evidence of recovery or plateau. The time latency before the expression of damage was dependent on both dose and the end point used. It was shorter the higher the dose. 51CrEDTA detected renal damage at the same doses as BUN but earlier in time, while %Hct showed evidence of renal damage at doses lower than both BUN and 51CrEDTA. Using the 51CrEDTA the dose-response curves for renal damage were steep and continuously shifting towards lower doses as follow-up time after treatment increased. There was a sparing effect of reducing the dose rate that was more evident at follow-up times of less than a year than at 66 weeks after TBI. Thus, the dose modifying ratio (DMF), defined as the dose needed to cause renal damage in 50% of irradiated animals (ED50) using LDR divided by the ED50 using HDR, was dependent on the time of evaluation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Quality assurance in radiotherapy. European Society for Therapeutic Radiology and Oncology Advisory Report to the Commission of the European Union for the 'Europe Against Cancer Programme'.
This document is now in the process of being endorsed by all National Scientific Societies of Radiotherapy and Medical Physics of the European countries. It can therefore not be formally considered as the definitive version and is still susceptible to benefit from further alterations or improvements.
Clinical Competence↗
About tolerance and quality. An important notice to all radiation oncologists.
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Dose-Response Relationship, Radiation↗
Selective assessment of in vitro radiosensitivity of tumour cells and fibroblasts from single tumour biopsies using immunocytochemical identification of colonies in the soft agar clonogenic assay.
The assumed selective growth of tumour cells has formed the basis for the use of the soft agar clonogenic assay to test in vitro radio- and chemosensitivity of tumours. However, recent studies have demonstrated that fibroblasts proliferate in soft agar in addition to tumour cells. The present study was initiated to quantify the contaminating growth of non-malignant cells in the modified form of the Courtenay-Mills soft agar assay, in order to establish a reliable assay for estimating tumour cell radiosensitivity in squamous cell carcinomas of the head and neck. DNA flow cytometry analysis confirmed that 'tumour fibroblasts' (fibroblasts obtained from tumour biopsies) grow in soft agar. In contrast, white blood cells did not form colonies. Different media were tested with soft agar, but a selective medium for tumour cells was not found. Therefore, a colony filter-technique combined with an immunocytochemical analysis was developed to quantify the number of tumour cell and fibroblast colonies. In 12 tumour biopsies, 2-33% of the colonies were Cytokeratin AE1-3 positive, whereas 83-100% of the colonies were 5B5 fibroblast antibody positive. The parameter normally reported, the overall SF2 (surviving cell fraction at 2 Gy) based on colonies in agar, was found to be statistically significantly correlated to the fibroblast SF2, but not to the tumour cell SF2. The overall SF2 was significantly different from the tumour cell SF2 in half of the tumours. Furthermore, the tumour cell SF2 was not correlated to fibroblast SF2. In consequence of our findings, correcting for fibroblast contamination is a necessity, when studying in vitro sensitivity of tumour cells. Combining the soft agar clonogenic assay with the new colony filter-technique and the immunocytochemical analysis appear to be useful for making this routine correction and for measuring the in vitro radiosensitivity of both tumour cells and fibroblasts from single tumour biopsies, which is of interest in future clinical studies on predictive assays.
Biopsy↗
Late renal damage after total body irradiation and bone marrow transplantation in a mouse model: effect of radiation fractionation.
In response to the accumulating evidence that renal damage is now becoming an important late complication after total body irradiation (TBI) and bone marrow transplantation (BMT), we have tested the effect of fractionated and hyperfractionated TBI on late kidney damage in a mouse model. TBI was given as fractionated (three fractions in 3 days, Fx 3), or hyperfractionated (nine fractions in 3 days, Fx 9) treatment. Kidney damage was evaluated using [51Cr]EDTA residual activity, blood urea nitrogen (BUN) and percentage haematocrit (%Hct) as end-points. We were able to detect progressive renal damage with no evidence of recovery or plateau in the Fx 3 and Fx 9 schedules. The time latency before the expression of renal damage was dependent on both total dose and end-point and it was shorter the higher the dose. [51Cr]EDTA detected renal damage at the same doses as BUN but earlier in time whereas %Hct detected renal damage at doses lower than both BUN and [51Cr]EDTA. Reducing the dose per fraction spared the kidney from TBI damage. The dose-response curves for renal damage (using the [51Cr]EDTA end-point) were steep, and tended to shift towards lower doses with longer follow-up times. The dose-modifying factors defined as the dose needed to cause renal damage in 50% of the animals (ED50) using single fraction TBI divided by the ED50 using fractionated TBI were 1.3 and 1.9 for the Fx 3 and Fx 9, respectively. These results may indicate that patients treated with TBI and BMT should be assessed for late kidney damage and that fractionation and particularly hyperfractionation may protect the kidneys from TBI-induced renal damage.
Animals↗
Direct evidence that hydralazine can induce hypoxia in both transplanted and spontaneous murine tumours.
Hydralazine can substantially decrease blood flow and increase hypoxia in transplanted tumours. Previous indirect studies have suggested that hydralazine does not induce such effects in spontaneous tumours. We have now directly investigated the ability of hydralazine to increase hypoxia in both transplanted and spontaneous murine tumours by measuring tumour oxygen partial pressure (pO2) distributions using an Eppendorf oxygen electrode. Spontaneous tumours arose at different sites in CDF1 mice, while transplanted tumours were produced by implanting a C3H mouse mammary carcinoma on the backs of the same mouse strain. Measurements of pO2 were made in anaesthetised mice immediately before and 45 min after an intravenous injection of 5 mg kg-1 hydralazine. In the transplanted tumours hydralazine significantly decreased tumour oxygenation, such that the percentage of pO2 values < or = 5 mmHg increased from 45% to 87%, and median pO2 decreased from 5 to 3 mmHg. Similar significant changes were induced by hydralazine in the spontaneous tumours, the percentage of pO2 values < or = 5 mmHg increasing from 60% to 94% while the median pO2 values decreased from 8 to 2 mmHg. These results clearly show that there is no difference in the response of transplanted and spontaneous mouse tumours to hydralazine.
Adenocarcinoma↗
The effect of castration on tumor growth rate and cell kinetics in hormone sensitive and hormone insensitive rat prostatic adenocarcinomas.
Cell kinetics were measured in vivo in four experimental rat prostatic adenocarcinomas grown in normal or castrated rats. The aim was to investigate the effect of castration on growth rate and cell kinetics in hormone sensitive and hormone insensitive prostatic carcinomas. We used two anaplastic, hormone insensitive, fast growing tumors (Dunning R-3327-AT1 H and E), as well as two well differentiated, hormone sensitive, slow growing tumors (R-3327-H and R-3327-PAP). DNA ploidy, S-phase transit time (Ts), the labeling index (LI) and potential doubling time (Tpot) was determined by dual parameter flow cytometry, after in-vivo labeling, using bromodeoxyuridine (BUdR) and the tumor doubling time (DT) was determined from growth curves. After castration DT in the hormone sensitive H-subline changed from 21.7 days to 82.0 days, and in the PAP-subline from 22.2 days to 33.2 days. No significant changes in Tpot were observed. In the anaplastic tumors no differences in neither DT nor Tpot were seen. The cell loss factor (CLF) was relatively low in the two anaplastic tumors (0.55-0.59) compared to the well differentiated tumors. The CLF was unaffected by castration in the poorly differentiated tumors, whereas it increased significantly (from 0.75 to 0.92, P = 0.005) after castration in the H-tumor, and showed a non-significant increase in the PAP-tumor. This implies that the decrease in tumor growth in the hormone sensitive tumors is due to an increase in cell death, not a decrease in cell proliferation. These data indicate that CLF is the dominating factor in the reduced growth following androgen ablation in an androgen sensitive tumor. This study suggests that Tpot might be an additional predictor of a tumors proliferating rate and it may provide important information of the human prostatic cancer.
Adenocarcinoma↗
The importance of determining necrotic fraction when studying the effect of tumour volume on tissue oxygenation.
The relationship between tumour tissue oxygenation and necrosis at different tumour sizes was investigated in a C3H mammary carcinoma implanted in the feet of female CDF1 mice. Experiments were performed using tumours that ranged in size from 80 to 800 mm3. Necrosis was estimated histologically. Tumour tissue oxygenation (pO2) was estimated with an Eppendorf electrode. Our results showed that as tumour volume increased there was a corresponding increase in necrotic fraction ranging from 1% in small tumours up to 51% in large tumours. The percentage of pO2 values < or = 5 mmHg increased from 2% up to 79%, in small and large tumours respectively. After correcting for necrosis, the apparent, significant increase in the % of pO2 values < or = 5 mmHg was lost. We conclude that correcting for necrotic fraction in this tumour model is necessary when attempting to measure tumour oxygenation using electrodes.
Animals↗
Reoxygenation in a C3H mouse mammary carcinoma. The importance of chronic rather than acute hypoxia.
The role that chronic and acute hypoxia play in tumour reoxygenation after irradiation was investigated in a C3H mouse mammary carcinoma grown in the feet of female CDF1 mice. Tumours at 200 mm3 in size were locally irradiated with a priming dose of 20 Gy and then at various times after given a range of radiation doses under normal or clamped conditions. Local tumour control was determined 90 days later from which the tumour hypoxic fractions were calculated. Untreated tumours contained 23% hypoxic cells. Immediately after 20 Gy this increased to 52% and by 24 h had fallen to 10%. These reoxygenation experiments were repeated, giving either nicotinamide (1000 mg/kg; i.p. injected 30 min before each irradiation) to remove acute hypoxia, or carbogen breathing (for 5 min before and during irradiation) to decrease chronic hypoxia. With nicotinamide the normal hypoxic fraction was reduced to 7%, but after irradiation it had risen to 46% and by 24 h there was full reoxygenation with a value of 5% being observed. Carbogen breathing also decreased the normal hypoxic fraction to 6%, and immediately after irradiation this was increased to 38%. However, by 24 h it was still elevated at around 23%. These results suggest that chronic rather than acute hypoxia is necessary for reoxygenation in this tumour.
Animals↗
Relationship between tumour oxygenation, bioenergetic status and radiobiological hypoxia in an experimental model.
Tumour oxygenation and bioenergetic status were measured in the same tumour and these results related to radiobiological hypoxia. A C3H mouse mammary carcinoma grown in the feet of CDF1 mice was used. Bioenergetic status was assessed by 31P MRS using a SISCO 7 Tesla magnet, oxygen measurements were done by a polarographic electrode and the hypoxic fraction was determined from direct analysis of the radiation dose-response data. During all examinations restrained, non-anaesthetized mice were allowed to breathe either 100% oxygen, carbogen, normal air, carbon monoxide (CO) at 75, 220, or 660 ppm or had blood flow occluded by clamping. Results showed a significant correlation between the radiobiological hypoxic fraction and % pO2 < or = 5 mmHg under the different treatment conditions, whereas no correlation was found between beta nucleosidetriphosphate/inorganic phosphate (beta-NTP/Pi) ratio and either the hypoxic fraction or the % of pO2 values < or = 5 mmHg under the different treatment conditions. In conclusion, oxygen electrode measurements were sensitive to changes in tumour hypoxia whereas the bioenergetic status alone seemed to be a less precise measure of hypoxia in this tumour model. Furthermore, the present study demonstrated that tumour cells in vivo can actually maintain the bioenergetic status during a period of severe hypoxia.
Animals↗
The ability of nicotinamide to inhibit the growth of a C3H mouse mammary carcinoma.
Experimental studies have suggested that nicotinamide and its analogs may inhibit the growth of murine tumours. We have now investigated this using a C3H mouse mammary carcinoma implanted into the right rear foot of female CDF1 mice. From days 1 to 30 after implantation mice were intraperitoneally (i.p.) injected with either 100, 200, 500 or 1,000 mg/kg nicotinamide. The tumour volume (+/- 1 S.E.) after 30 days in saline-treated mice had reached 1540 mm3 (+/- 260). No change in tumour growth was seen at that time with daily doses of up to 500 mg/kg nicotinamide, but at 1,000 mg/kg tumour volume was reduced to 904 mm3 (+/- 233). However, this large dose of nicotinamide was also toxic to the mice with some 16% of animals dying during the 30-day treatment period. A similar growth inhibition was seen with daily i.p. injections of 5 mg/kg fumagillin (tumour volume at 30 days = 821 +/- 191 mm3), a known inhibitor of angiogenesis, but whether this mechanism also explains the nicotinamide effect is not clear.
Animals↗
Prognostic value of pretreatment factors in patients with locally advanced carcinoma of the uterine cervix treated by radiotherapy alone.
The prognostic effect of pretreatment patient- and tumor characteristics, and the influence of radiotherapy schedule on local control, distant metastases, and crude survival were analyzed in 424 consecutive patients with FIGO stage IIB (n = 137), IIIA (n = 10), IIIB (n = 211) and IVA (n = 66) cancer of the uterine cervix. All patients were given radiotherapy alone. From 1974 and through 1977, the external and intracavitary combined radiotherapy was given continuously in 4 to 6 weeks. From 1978 and through 1983, the treatment policy was changed to split-course radiotherapy by introducing planned pauses, resulting in an overall treatment time of 10 to 12 weeks. The results were estimated by univariate actuarial- and Cox multivariate regression analyses. Multivariate analysis showed that significant adverse variables for local control were large lateral tumor diameter, young age, low hemoglobin at time of admission, many pregnancies, split-course strategy, and high FIGO stage. Risk of metastases increased with decreasing hemoglobin, increasing malignancy grade and split-course treatment. Poor survival probability were related to large lateral tumor diameter, high malignancy grade and FIGO stage, low hemoglobin, split-course therapy, and adeno/adenosquamous tumor type.
Actuarial Analysis↗
A century with hyperthermic oncology in Scandinavia.
The hyperthermic research during the last 100 years is reviewed with the aim to describe a research activity which has been performed in parallel to and associated with the development of radiation oncology. Basic and clinical research in several Scandinavian centres has made major international contributions to the establishment of a rationale for and implementation of hyperthermia as a combined modality treatment with chemotherapy or radiation in oncology. At the same time it has been demonstrated that collaboration and integration easily could be performed within the Scandinavian centres. Hyperthermic oncology is therefore a typical example of how research involving both biological, physical/engineering, and clinical skills in a proper environment can create valuable results.
History, 20th Century↗
The in vivo interaction between vincristine and radiation in a C3H mammary carcinoma and the feet of CDF1 mice.
PURPOSE: Evaluation of the interaction between vincristine (VCR) and X rays in a murine tumor and its surrounding skin. METHODS AND MATERIALS: End points were local tumor control and moist desquamation using the C3H mammary carcinoma and the mouse foot skin in vivo. Cell cycle effects of VCR was studied by dual parameter flowcytometry. Vincristine was administered as a single IP injection at various time intervals from 4 days before to 4 days after irradiation. RESULTS: Flowcytometric studies of cell cycle distribution showed that VCR caused a temporary blockage of cells in the mitotic phase; the proportion of cells in G2M increased three-fold at intervals up to 48 h after VCR treatment. The radiation enhancement peaked when VCR was administered 24 h before X rays in tumors, and when given 15 min before X rays in skin. A significant therapeutic gain was observed at the 24 h preirradiation of postirradiation intervals--the therapeutic gain factors being 1.19 and 1.24, respectively (p < 0.005). Analysis of the tumor data suggested an additive cytotoxic effect rather than VCR radiosensitization. In contrast to what was expected from the single dose data, a significant loss of therapeutic effect was found for the addition of VCR administered at the first day of a fractionated irradiation regime with five fractions in 5 days (p < 0.025). CONCLUSION: The tumor control studies showed a lack of correlation between the VCR-induced accumulation of cells in G2M cell cycle phase and enhancement of tumor radiation response. Preirradiation VCR caused radiosensitization both in tumors and skin, whereas postirradiation VCR mostly resulted in responses equal to radiation only.
Animals↗
Early and late radiotherapeutic morbidity in 442 consecutive patients with locally advanced carcinoma of the uterine cervix.
PURPOSE: to evaluate the early and late radiotherapeutic morbidity after combined external and intracavitary radiotherapy to the uterine cervix. METHODS AND MATERIALS: The morbidity in 442 consecutive cervical cancer patients FIGO Stage IIB (139), IIIA (10), IIIB (221) and IVA (72) treated from 1974 to 1984 were recorded retrospectively according to our own previously described system (18). This system is based on the assumption that radiotherapeutic morbidity progresses in severity with time wherefore successive morbidity scoring rather than recording the maximal damage alone is required to estimate the burden of complications for a group of patients. The early and late morbidity (within or beyond 3 months after the end of radiotherapy) was graded into mild, moderate, severe, and causing death depending on the symptoms and signs, and the requirement and type of therapy. The late morbidity was characterized by both the frequency and the actuarially corrected estimate. Also, the combined morbidity in two, three, four and five organs and the probability of surviving without tumor recurrence and/or significant late morbidity were evaluated. RESULTS: Early morbidity was most frequently seen in the rectosigmoideum (61%) and urinary bladder (27%). Medication for early morbidity was required in 68% and hospitalization in 10% of the patients. The frequencies of each late morbidity grade did not differ in relation to FIGO Stage while the actuarial estimates increased significantly with increasing stage. This reflects the poor prognosis in the more advanced stages, where few patients survived to develop late morbidity, and also points to the importance of latency in reporting late radiotherapeutic morbidity. In Stage IVA patients, the ratios between the actuarial estimate and the frequency of late severe rectosigmoid and urinary bladder morbidity were as high as 2.5 and 3, respectively. The highest 5-year risks (+/- 1 SE of the estimate) of late severe morbidity were found for the rectosigmoideum (28% +/- 3), small intestine (13% +/- 2) and urinary bladder (10% +/- 2). Rectosigmoid and urinary bladder complications constituted the most important part of the combined organ morbidity. Almost half of the patients developing late moderate rectosigmoid and one-third of those developing late moderate bladder complications, did so within one year after radiotherapy. Almost all complications were developed within 3 to 4 years after radiotherapy. The probability of surviving without recurrence and/or severe combined rectosigmoid and urinary bladder morbidity was low (23% +/- 2). CONCLUSION: Actuarial estimates rather than frequencies should be reported to avoid underestimation of the risk of late radiotherapeutic morbidity in long-term survivors.
Adult↗
Relationship between radiobiological hypoxia in tumors and electrode measurements of tumor oxygenation.
PURPOSE: To determine whether electrode measurements of tumor oxygenation, made in a variety of murine tumor models, correlate with estimates of radiobiological hypoxia in the same tumor systems. METHODS AND MATERIALS: The tumor models used were a C3H mammary carcinoma grown in the feet of CDF1 mice; the SCCVII, KHT and RIF-1 tumors grown in the feet or flanks of C3H/Km mice; and the CaNT and SaF tumors grown on the backs of CBA mice. All treatments were performed when tumors were about 200 mm3 in size. Radiobiological hypoxic fractions were determined using either a paired survival curve assay, with survival measured 0-24 h after irradiation, or using a clamped tumor control assay, with percent local tumor control estimated 90 days after treatment. Measurements of tumor oxygen partial pressure (pO2) distributions were performed using Eppendorf oxygen electrodes. RESULTS: The hypoxic fractions determined from the radiation response data were about 1% in RIF-1 and SCCVII, 12% in C3H and KHT, 28% in CaNT and up to 38% in SaF tumors. When this data was compared with the tumor oxygenation measurements it was found that as hypoxic fraction increased the mean, median, and the percentage of pO2 values < or = 5 mmHg showed a trend towards poorer oxygenation status. However, none of these pO2 changes were significantly correlated with hypoxia. Moreover, the pO2 values < or = 2.5 mmHg indicated an improvement in oxygen status with increasing hypoxic fraction. CONCLUSION: Electrode measurements of tumor oxygenation alone may, therefore, not be a good indicator of tumor hypoxia across different tumor cell lines.
Animals↗