Hyperthermia in clinical oncology.
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Humans↗
Biomedical subjects
J Overgaard
Publications and source records attributed to J Overgaard.
Primary radiotherapy of T1 squamous cell carcinoma of the larynx: analysis of 478 patients treated from 1963 to 1985.
Radiotherapy was administered to 478 consecutively treated patients with laryngeal T1 squamous cell carcinoma between 1963-1985. One hundred and seventeen had a supraglottic, 358 a glottic, and 3 a subglottic tumor. Supraglottis: 71% males; 49% T1a; 14 patients with nodes. Glottis: 90% males; 82% T1a; 1 patient with node. The 10-year value for local control in the supraglottic group was 55% and in the glottic group 81%. No difference was observed between T1a and T1b. Regional nodes and distant metastases were seldom seen in the glottic, but frequently observed in the supraglottic group. The treatment results appeared to be most favorable in women. The 10-year corrected survival for supraglottic and glottic tumors demonstrated a highly significant difference, 67% compared to 94%. There was a significantly increasing incidence of events with lower tumor differentiation. Split-course and conventional radiotherapy gave equal treatment results, but late complications were significantly more common with the former. A major problem was new primary cancers, which within 20 years occurred in 34% of patients surviving a supraglottic tumor and in 23% of the glottic patients. The predominant new site was the lung (23% and 13%, respectively). Thus, in the glottic group more patients died from the new cancer than from the glottic carcinoma.
Adult↗
Cytotoxic effect of misonidazole and cyclophosphamide on aerobic and hypoxic cells in a C3H mammary carcinoma in vivo.
The chemosensitising effect of the nitroaromatic radiosensitiser misonidazole (MISO) on the alkylating agent cyclophosphamide (CTX) has been investigated in a C3H mammary carcinoma in CDF1 mice. The selective cytotoxicity against aerobic and hypoxic cells was measured indirectly, using a local tumour control (TCD50) assay. The hypoxic fraction was calculated from the dose difference between the TCD50S for tumours irradiated either in air or under clamped conditions. The relative survival of tumour cells after drug therapy was expressed as a surviving fraction (SF). CTX (100 mg kg-1) was found to be considerably more toxic towards hypoxic than aerobic cells (SF 4% versus 52%). MISO (1000 mg kg-1) was almost exclusively toxic to hypoxic cells (SF 22%). When MISO and CTX were administered simultaneously a decrease in the surviving fraction was observed. The effect on aerated cells was found to be 10-fold more than expected from addition of toxicities, suggesting a chemosensitising effect on these cells by MISO when used in combination with CTX. No synergistic effect was found on radiobiologically hypoxic cells. The exact role of hypoxia for the development of chemosensitisation seems to be complex and requires additional research in the future.
Animals↗
Does variation in the in vitro cellular radiosensitivity explain the shallow clinical dose-control curve for malignant melanoma?
In radiotherapy, clinical dose-control curves are generally more shallow than what should be expected from in vitro dose-survival curves for human cells of the same histology. One possible explanation is that a considerable inter-tumor heterogeneity in radiosensitivity flattens out the presumably steep individual dose-control curves. This paper compares dose-control curves for malignant melanomas derived from clinical data with curves derived from in vitro cell-survival experiments. Although inter-tumour variability in the in vitro dose and fractionation sensitivity may explain parts of the discrepancy between the steepness of clinical and in vitro dose-control curves, the present calculation indicates that a considerable additional variability, undetected by current in vitro assays, must be assumed to exist in order to resolve the discrepancy.
Cell Survival↗
Relation between angiographic cerebral vasospasm and regional CBF in patients with SAH.
The relation between angiographically determined cerebral vasospasm following a subarachnoid hemorrhage and regional cerebral blood flow (CBF) was studied in 63 investigations of 45 patients. The CBF was measured using the intra-arterial 133-Xe clearance technique within one hour of angiography. A positive correlation between regional CBF and diameter of major supplying vessel was observed. However, in the 13 cases with focal vasospasm the reduction in CBF was global and not restricted to the area of the spastic vessel. The cerebral oxygen extraction was reduced but independent of the degree of vasospasm, speaking against vasospasm as the cause for the reduction in CBF. The observed association between reduction in CBF and vasospasms could be caused by a common factor responsible for development of both. Thus, it is proposed that the amount of blood escaping at time of aneurysm rupture determines 1) the amount of reduction in cerebral oxygen uptake and thereby the reduction in CBF and 2) the degree of vasospasm. If so a correlation, yet not causal, between reduction in CBF and degree of vasospasm, will be observed.
Cerebral Angiography↗
Squamous cell carcinoma of the oropharynx: an analysis of 213 consecutive patients scheduled for primary radiotherapy.
Radiotherapy was administered to 213 consecutively treated patients with oropharyngeal squamous cell carcinoma. The classification (Union Internationale Contre le Cancer, 1982) showed primary tumors (T1, 13%; T2, 51%; T3, 34%; T4, 2%) and regional lymph nodes (N0, 38%; N1, 38%; N2, 4%; N3, 20%). The 10-year actuarial value for local control was 48%; for regional control, it was 66%. Distant failure occurred in 20 patients. The 10-year actuarially corrected survival rate was 40% (stage I, 57%; stage II, 51%; stage III, 43%; stage VI, 21%). Locoregional tumor control was significantly influenced by irradiation parameters (total dose and treatment time), tumor volume, sex, and hemoglobin value. It is concluded that local control of the tumor while still in the T position is the parameter most crucial to success. This end point is currently being aimed at evaluating primary surgery and testing a radiation technique with larger total doses and shrinking fields and a new radiosensitizer, while at the same time investigating the influence of hemoglobin concentration.
Adult↗
The in vivo response of a C3H mammary carcinoma to treatment with misonidazole, cyclophosphamide and radiation.
The potential chemosensitizing effect of the nitroaromatic radiosensitizer misonidazole (MISO) on the alkylating agent cyclophosphamide (CTX), and the interactions of these agents with radiation, have been investigated in a C3H mammary carcinoma in CDF1 mice. MISO at 1,000 mg/kg caused a small increase in tumour growth time (TGT; time to reach 3 times treatment volume) from 3.6 days to 4.5 days. CTX (100 mg/kg) increased the TGT to 15.7 days. The combined treatment of MISO and CTX given with intervals of either 15 min or 4 h increased the TGT to 23.3 and 23.8 days respectively. The radiation enhancement ratio (ER) was found to be 2.13 and 1.10 for MISO administered before or after x-rays respectively. The corresponding ERs for CTX were 1.16 and 1.22. The two drugs given in combination resulted in significant radiation ERs of 2.68 (both drugs given within 30 min before x-rays), 3.00 (MISO 30 min before and CTX 3 1/2 h after x-rays) and 1.40 (both drugs given after x-rays). In contrast to what has previously been reported, and in contrast to the tumour regrowth delay data, the results of the tumour control experiments were found to reflect no more than an additive action of the two drugs when used together with radiation in vivo.
Animals↗
[Radiation enteritis: mucosal regeneration and stromal reaction of the small intestine after irradiation].
D-glucose absorption in vivo in mice decreased as a function of dose and time after irradiation returning to normal within a week after irradiation. The lamina propria is seen full of polymorphonuclear leukocytes, other infiltrative cells, capillary and lymphatic network, which seem closely related to chronic enteritis. Since acute and chronic diarrhea after irradiation can be reduced by cholestyramine or acetylsalicylate, malabsorption of bile salts or prostaglandin E of the luminal content has been regarded as a cause of radiation-induced diarrhea. LD 50 of irradiated mice was increased by SOD. From the clinical data, thin physique, previous operation, and total dose of more than 50 Gy could be predisposing factors of radiation-related enteritis.
Adult↗
The influence of radiation dose on the magnitude and kinetics of reoxygenation in a C3H mammary carcinoma.
The variation in hypoxic fraction as a function of time after various priming doses of radiation has been investigated in a C3H mouse mammary carcinoma in situ. The hypoxic fraction was calculated from data for local tumor control. Untreated tumors were found to contain 4.8% radiobiologically hypoxic cells. Within minutes after a priming dose of 20 Gy given in air, the hypoxic fraction increased to a value not significantly different from 100%. After 4 h, reoxygenation was complete (hypoxic fraction 1.3%), and the hypoxic fraction stabilized at a level significantly below the untreated value. Following a priming dose of 40 Gy the reoxygenation pattern was different: The hypoxic fraction stayed above the pretreatment value for 4 h, and pronounced reoxygenation occurred after 12 h (hypoxic fraction 0.4%). At longer time intervals the hypoxic fraction again increased to--and slightly above--the oxygenation level of untreated tumors. The present findings show that reoxygenation in solid tumors is a function of radiation dose, and the data suggest that mechanisms other than a decrease in tumor cell O2 consumption are involved in tumor reoxygenation.
Animals↗
[Prognosis in synchronous liver metastasis from colorectal cancer. A multicenter study of patients with cancer of the rectum and cancer of the rectosigmoid colon].
A prospective investigation of 188 patients with cancer of the rectum and rectosigmoid colon with synchronous liver metastases is described. The mean survival time for 183 patients who did not receive any treatment for the liver metastases was six months and only one survived for longer than 37 months. After extirpation of the primary tumour, the most significant prognostic factors were etrahepatic metastases, enlarged liver on account of metastases and more than three liver metastases. Serum basic phosphatases had the greatest significance among a series of laboratory tests. In the sub-groups with the best possible prognoses, the mean survival time was 12 months. 25% five-year survival has been described in the literature following resection of the liver in patients with a maximum of three metastases, no other metastases and age under 70 years. Provided this holds true, liver surgery will be a therapeutic possibility in at least 100 patients per annum in Denmark with synchronous liver metastases and 25 of these will be cured. This figure requires an improved programme for the diagnosis of synchronous liver metastases than at present and the same high frequency of extirpation of the primary colorectal cancer on a national basis which was achieved in the present material.
Aged↗
Clinical radiobiology of malignant melanoma.
Tumor-control probability (TCP) was analyzed in a series of 121 patients having 239 histologically proven recurrent or metastatic malignant melanomas. These were treated with fractionated radiotherapy with various doses per fraction, total doses, and overall times. Cutaneous lesions (127, 53%) were treated with electron beams, and more deeply seated tumors (112, 47%) with 60Co or 4-8 MV X-rays. The fraction size was highly variable, and this permitted determination of the alpha/beta ratio in the multifraction linear-quadratic model, which was estimated at 0.57 Gy with 95% confidence limits [-1.07, 2.5] Gy. Treatment time had no demonstrable influence on TCP. Thus this tumor exhibits the fractionation sensitivity characteristic of a late-responding normal tissue, suggesting that an adequate fractionation schedule for malignant melanomas would be characterized by larger-than-conventional doses per fraction, possibly about 6 Gy per fraction. This is consistent with the conclusions of other authors. Tumor size, evaluated as mean tumor diameter, S, had a major impact on TCP: the number of target cells increased as a power function of S with exponent 0.72 (95% confidence limits [0.49, 0.94]. In fact, a considerable amount of the heterogeneity in the dose-response data could be removed by accounting for size. Thus, the weak or absent dose response became highly significant. When a patient had multiple lesions, the responses of these to radiotherapy tended to be similar, thus implying that results were significantly influenced by a "hidden parameter" (such as inherent radiosensitivity or immunological status). A test of the predictive value of the TCP-model was performed in a different series of 183 cutaneous and lymph node malignant melanomas. The observed dose-response relationship in this data set was in good agreement with the model prediction. A chi-square test for goodness-of-fit showed that the variation between predicted and observed results could be explained by the binomial variation on quantal response data.
Cobalt Radioisotopes↗
Cystometric evaluation of early and late irradiation damage to the mouse urinary bladder.
The present study reports a simple, non-invasive, in vivo method for detecting early and late radiation damage to the mouse urinary bladder using transurethral bladder filling. The study also describes a useful experimental model for irradiation of mouse urinary bladder without any concomitant irradiation of the rectum and bony structures and maximal shielding of the small intestine. Within 30 days after single fraction bladder irradiation at 5-30 Gy, repeated cystometric investigations reveal a change in the reservoir function of the bladder illustrated by a considerable dose-dependent decrease in the compliance of the bladder wall. The changes in the reservoir function is reversible hence the bladder function is restored after another month. At various time intervals after the irradiation, however, the late radiation damage appears, the time of manifestation being dose-dependent. This final change is irreversible and consistent with the clinically known contracted bladder.
Animals↗
Radiosensitization by nicotinamide in tumors and normal tissues: the importance of tissue oxygenation status.
Nicotinamide induced radiosensitization of tumors has been suggested to be a consequence of a reduction in tumor hypoxia. We have investigated the possibility that nicotinamide may produce significant radiosensitization in a normal tissue in which the radiation response is also influenced by hypoxia. The normal tissue studied was testis and radiation damage was assessed by measuring survival of spermatogonial stem cells. The radiosensitizing action of nicotinamide in testis was compared to that observed in a C3H mammary carcinoma when assayed by both regrowth delay and local tumor control. Our results show that nicotinamide (1000 mg/kg; i.p.) enhanced radiation damage in both tissue types when the radiation was given up to at least 3 hr after drug injection. Enhancement ratios obtained when the drug and radiation were separated by a 1 hr time interval were between 1.1 to 1.2 for the testis and 1.0 to 1.5 for the tumor. The results suggest that nicotinamide will produce radiosensitization in testis, but the effect is small and less than that observed in tumors.
Animals↗
The current and potential role of hyperthermia in radiotherapy.
Current clinical experience strongly suggests that hyperthermia will become an important modality as an adjuvant to radiotherapy in the treatment of locally advanced solid tumors. Hyperthermia must therefore be considered a topic of general interest. Biologically, hyperthermia has two different types of interactions with radiation. Firstly, heat has a radiosensitizing effect. This is most prominent with simultaneous application, but is of the same magnitude in both tumor and normal tissue and will not improve the therapeutic ratio unless the tumor is heated to a higher temperature than the normal tissue. Secondly, hyperthermia exhibits a direct cytotoxic effect, and a moderate heat treatment alone can almost selectively destroy tumor cells in a nutritionally deprived chronically hypoxic and acidic environment. Because such cells are the most radioresistant, a smaller radiation dose is needed to control the remaining more radiosensitive cells. If critical, irradiated normal tissues are also heated, the cytotoxicity is best utilised if heat is given at least 3-4 hours after irradiation. The magnitude of both the sensitizing and the cytotoxic effect depends on temperature and heating time. Clinically, heating of superficial tumors (e.g. breast, neck nodes and malignant melanoma) has confirmed the biological rationale for using hyperthermia as an adjuvant to radiotherapy. An overview of available data gives thermal enhancement ratios of approximately 1.5 in several superficial tumor sites after external heating. From a practical point of view, true simultaneous treatment is almost impossible using external heating, and the major effect of the combined treatment will have to rely on hyperthermic cytotoxicity. This makes the design of clinical schedules less complicated since only a few heat fractions may be needed to achieve an optimal effect. On this basis, several randomized clinical trials have been activated with the aim to evaluate the role of adjuvant hyperthermia in the primary treatment of advanced (superficial) tumors. In addition, studies are underway to specifically elucidate the clinical relevance of thermotolerance and other biological issues. So far, the clinical evaluation has almost solely been limited to superficial tumors, or to situations where interstitial heating is feasible. External heating of "deep" seated tumors is still preliminary, and most studies are in Phase I-II, with emphasis on toxicity and feasibility. The initial results are promising with regard to improved tumor control and acceptable toxicity.
Combined Modality Therapy↗
Misonidazole combined with split-course radiotherapy in the treatment of invasive carcinoma of larynx and pharynx: report from the DAHANCA 2 study.
Between October 1979 and May 1985, 626 patients with pharynx and larynx carcinoma were randomized to two different split-course radiation regimens and given either misonidazole (MISO; 11 g/m2) or placebo during the initial 4 weeks of treatment. Patients in the different treatment groups were evenly distributed among stages. The small number of females (136) gave an uneven distribution, thus making analysis difficult. The results show that females had a statistically better loco-regional control (45 vs. 33%; 5-year actuarial value). Overall, the MISO treated group did not have a significantly better control rate than the placebo groups (37 vs. 34%). However, a difference was found in patients with pharynx carcinomas (38 vs. 27%; p less than 0.05). The pre-irradiation hemoglobin (Hb) concentration was found to be a prognostic parameter. In females, loco-regional control for IIb values below or above 8 mmol/l were 37 and 47%, respectively. In males, the same values were below or above 9 mmol/l 26 and 38%. Hb influence on local control was only seen in supraglottic and pharynx tumors. This effect was independent of tumor size, which also was of prognostic value. In addition Hb concentration and MISO had an apparent additive effect. Thus in the male pharynx group, placebo patients with low Hb had a 14% disease rate compared to 40% in MISO treated patients with Hb above 9 mmol/l. MISO induced significant peripheral neuropathy in 26% of the treated patients, whereas other drug related side effects were minimal and tolerable.
Carcinoma, Squamous Cell↗
Misonidazole combined with radiotherapy in the treatment of carcinoma of the uterine cervix.
Between April 1979 and January 1982, 331 patients were included in a study to establish whether misonidazole (MISO) had any effect as an adjuvant to radiotherapy in the treatment of squamous cell carcinoma of the uterine cervix (FIGO Stage IIb, III, and IVa). Patients were randomized to receive either MISO (12 g/m2 applied within 6 weeks) or placebo. This was given in conjunction with each institution's normal radiotherapy schedule and thus varied with regard to external and intracavitary irradiation. The analysis was performed based on patients' status at January 1986, with all patients observed for at least 4 years. One hundred and sixty-four patients received MISO and 167 placebo. Compliance to radiotherapy was good and MISO was well tolerated. The overall rates for MISO vs. placebo were as follows: local tumour control, 50 vs. 54%; disease-free survival, 47 vs. 46%, and crude survival, 39 vs. 45%. A similar lack of MISO effect was found in the individual stages. However, patients in all stages with hemoglobin concentrations below 7 mmol/l had a significantly lower local control probability (overall 24 vs. 47%), whereas the incidence of distant metastases was unaffected. We conclude that the addition of MISO did not influence the radiation response in advanced uterine carcinoma. The reasons for this ineffectiveness are yet to be clarified.
Carcinoma, Squamous Cell↗
Early and late normal-tissue injury after postmastectomy radiotherapy alone or combined with chemotherapy.
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Antineoplastic Combined Chemotherapy Protocols↗
Sensitization of hypoxic tumour cells--clinical experience.
There is substantial evidence for the presence of hypoxia in human tumours. This is documented by histopathological demonstration of vascular insufficiency, direct oxygen measurements in tumours, as well as by physiological imaging and mapping of hypoxic areas. As a consequence, clinical trials have focused on the hypoxia problem for more than 30 years. This includes the use of hyperbaric oxygen, hypoxic cell radiosensitizers, and, more recently, modification of the oxygen-unloading capacity of haemoglobin. Agents directed towards destruction of hypoxic cells have also been applied, such as hyperthermia and bio-reductive drugs. Despite decades of clinical trials, the results are still inconclusive, and although some trials have shown significant benefit, it has become apparent that hypoxia is a complex problem. Hypoxia appears to be especially a problem in certain tumour types (e.g. squamous cell carcinoma), but even within tumours of the same type, site, and stage, hypoxia does not occur to the same extent. Furthermore, there are increasing suggestions that hypoxia may occur in two principally different ways, namely acutely and chronically, yielding varying responses to modifying agents. Although improvement in hypoxic cell radiosensitizers and other agents is under way, a definitive solution to the hypoxia problem will not be found until the tumours in which hypoxia occurs can be identified. This will require detailed analysis of individual tumours and patients' parameters, and better knowledge of the mechanisms of reoxygenation in clonogenic tumour cells.
Cell Hypoxia↗