Different fractionation schemes tested by histological examination of autopsy specimens from lung cancer patients

The biological effects of different fractionation schemes have been evaluated by the histological examination of bronchial carcinomas removed at operation or autopsy following radiotherapy. Radiation was given in daily, small fractions (200 cGy (rad)), large fractions (600 cGy (rad)) every fifth day, or a single high dose followed by daily low-dose treatment. The highest proportion of tumours free of viable cells was found in patients who had received small daily fractions in both operable and inoperable tumours. A hypothesis is put forward to explain this apparent change in radio-sensitivity with different fractionation schemes.     

52Fe for additional marrow ablation before bone marrow transplantation

The effectiveness of bone marrow transplantation (BMT) for malignant blood diseases remains limited by the inability of the preparative regimen to eliminate the disease without causing toxicity to normal organs. We have used 52Fe to deliver radiotherapy selectively to the BM. Fourteen patients with hematologic malignancies received 52Fe before a conventional BMT conditioning regimen. The median 52Fe dose was 58 mCi (range, 32 to 85 mCi). As evaluated by quantitative scanning, the median percentage of 52Fe taken up by the BM was 82% (range, 36% to 90%). This resulted in a median radiation-absorbed dose to the BM of 632 rad (range, 151 to 1,144 rad). The median uptake of 52Fe by the liver was 18% (range, 10% to 64%) and the median radiation-absorbed dose to the liver was 239 rad (range, 82 to 526 rad). The median whole body radiation-absorbed dose was 46 rad (range, 22 to 68 rad). No untoward effects were noted after the injections of 52Fe. The patients recovered hematopoiesis without toxicity in excess of that expected with conventional conditioning alone. The median follow-up was 8 months and three patients have relapsed. 52Fe should provide a way to boost the radiation dose to marrow-based diseases before marrow transplantation without increasing toxicity.     

Neurologic complications after irradiation of the cervical spinal cord for malignant tumour of the head and neck

A total of 165 patients with tumours of the head and neck were irradiated via fields including the entire cervical portion of the spinal cord. Eight patients (4.8 per cent) developed mild reversible signs of radiation myelitis. Only one of these cases was found among the 44 patients who received a dose to the spinal cord of over 5 000 rad via fields of less than 16 cm in length; 7 cases were patients with Hodgkin's disease who were given up to 3 700 rad via mantle fields. A survey of previous reports on transverse spinal lesions provoked by irradiation revealed a possibility of overdosage in several cases, and dose tolerance limits mentioned previously should accordingly be applied with caution.     

Follow-up study of patients treated by x-ray epilation for tinea capitis. Estimation of the dose to the thyroid and pituitary glands and other structures of the head and neck

This study is a further investigation of radiation dose to various head structures in the children given X-ray therapy for tinea capitis (ringworm of the scalp). In this work, estimates of the dose to the thyroid and pituitary gland were obtained with lithium fluoride thermoluminescent dosemeters using a child's head phantom. Doses were also measured for the parotid gland and several skin sites where skin tumours developed in the irradiated cases. In a previous study, brain and scalp doses of 140 and 500-800 rad had been estimated for the treated group using this same head phantom. In this work dosemeters were also placed in the same brain locations so that comparisons could be obtained between the two studies. The thyroid dose was estimated to be 6 +/- 2 rad and the pituitary dose was 49 +/- 6 rad for the conventional tinea capitis treatment. The dose to the parotid gland was 39 rad and the dose to skin sites on the face and neck where tumours occurred ranged from 20 to 40 rad. The data for the thyroid adenoma response from this and other studies involving irradiation of children suggests a linear dose-response relationship within the first 30-40 years after exposure with a risk of about 0-04% per rad.     

RBE of neutrons generated by 50 MeV deuterons on beryllium for control of artificial pulmonary metastases of a mouse fibrosarcoma

Artificial pulmonary metastases of a mouse fibrosarcoma were produced by the intravenous injection of 10(4) cells admixed with 2 X 10(6) plastic microspheres into mice preconditioned with 600 rad whole-body irradiation 24 hours earlier. Four days after injection of tumour cells, mice were irradiated with neutrons generated by 50 MeV deuterons on Be at the Texas A & M Variable Energy Cyclotron or with 137Cs gamma rays. One, three or six fractions of radiation were delivered on a three-hour fractionation schedule. Surviving lung metastases were scored macroscopically 16 days after irradiation. The data indicate that: (1) the RBE (n/gamma) was in the range 1.6-2.6 depending on the size of dose per fraction; (2) the slopes of the gamma-ray curves decreased with increasing fraction number (i.e. decreasing fraction size); (3) the slopes of the neutron curves decreased only slightly with increasing fraction number (and decreasing fraction size); (4) no additional sparing was achieved by further fractionating doses of neutrons of 300 rad or less.     

Medullomyoblastoma. A rare cerebellar tumour in children

Seven patients between the ages of 3 and 24 years were admitted to our hospital in the last 28 years who had a histological diagnosis of medullomyoblastoma. These patients presented with classic symptoms of a posterior fossa midline mass associated with evidence of raised ICP. A CT scan in each patient revealed a uniformly high-attenuating tumour in the posterior fossa with gross hydrocephalus. In all seven patients a ventriculoperitoneal shunt was placed prior to definitive surgery. Radical tumour excision was carried out in all cases 3-5 days after CSF diversion. The histological diagnosis was made on H&E-stained slides. In two cases each, the tumour tissue was subjected to electron microscopy and immunohistochemical studies. Six of the seven patients survived the operation. One patient died 21 days after surgery as a result of shunt block and shunt infection. All surviving patients received cranial and spinal radiation 2-4 weeks after surgery, and also chemotherapy. The cranial radiation dose ranged from 4500 to 5000 rad, while the spinal radiation dose was limited to 1500 rad. Patients were followed up carefully. Three patients died within 6 months, and the remaining three between 2.5 and 3 years after surgery. None of the patients in our study survived longer than 3 years. One patient had developed paraplegia. This study highlights the details of an uncommon entity and reports the largest collection of such cases in the literature.     

A short course - low dose preoperative irradiation of endometrial carcinoma. Preliminary report

This is a preliminary and comparative report of a randomized prospective study in which 14 unselected women with a proven histological diagnosis of endometrial adenocarcinoma were subjected to a course of external irradiation treatment with total 1,500 rad mid-pelvic dose delivered on five consecutive days followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy. Surgery was performed within 1 week after the completion of radiation therapy. At the same time, 15 additional patients with identical histological diagnosis were treated with the conventional external irradiation technique of 5,000 rad delivered in 5 weeks followed by surgery 6 weeks later. The stage indicates no significant differences between these two radiotherapeutic modalities in regard to survival rate, recurrences or complications. The short course-low dose approach markedly reduces the cost and overall treatment time.     

Radioembolization with 32P-labelled glass microspheres for advanced hepatocellular carcinoma

We evaluated the efficacy and side effect of 32P-Labelled glass microspheres (32P-GMS) as a radioembolizer for patients with advanced hepatocellular carcinoma (HCC). 24 patients with unresectable HCC received internal radiation treatment of 32P-GMS. The tumor size varied from 3.6 to 18 cm. Hepatic arterial embolization was carried out through intraoperative or Seldinger's method. The mean absorbed radiation dose of the liver was 3250 rad (range from 1200 rad to 8000 rad). The radiation intensity within the tumor was 3.3 times stronger than in liver tissue. Not significant bone marrow renal toxicity was noted within 1 to 3 months. > 50% of tumor shrinkage was found in 17 cases, and < 50% of tumor reduction in 5 cases. The cumulative survival rate of 3, 6, 12, 18, 24 months was 92%, 75%, 54%, 33% and 29%. Hepatic arterial instillation of 32P-GMS appears to be safe and effective for unresectable HCC even with portal vein thrombosis.     

Unequivalence between hemoglobin subunits. The effects of inositol hexakisphosphate on the absorption spectrum of liganded valency hybrids

Prophylactic hepatic irradiation was give to 28 "bad risk" Stage III Hodgkin's disease patients. The whole liver was given 2,000 rad in 10 days in addition to 1,800-2,000 rad to that portion included in the total nodal irradiation field. Twenty-three patients have been followed a minimum of 10 months with serial liver function tests. A transient elevation of serum enzymes has been noted at 3-12 months following hepatic irradiation in 78% (18 of 23 patients). No cases of clinical radiation hepatitis have been found in patients at risk 10 to 39 months (median, 23 months). Hepatic irradiation at this dose level appears to be tolerated without prohibitive complications.     

Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancer

PURPOSE: To evaluate the effect of mitomycin C to an accelerated hyperfractionated radiation therapy. The aim was to test a very short schedule with/without mitomycin C (MMC) with conventional fractionation in histologically verified squamous cell carcinoma of the head and neck region. METHODS AND MATERIALS: From October 1990 to December 1996, 188 patients entered the trial. Tumors originated in the oral cavity in 54, oropharynx in 82, larynx in 20, and hypopharynx in 32 cases, respectively. Patients' stages were predominantly T3 and T4 (158/188, 84%) and most patients had lymph node metastases (144/188, 77%) at diagnosis. Only 22 patients were female, 166 were male, the median age of patients was 57 years (range 34 to 76 years). Patients were randomized to one of the following three treatment options: conventional fractionation (CF) consisting of 70 Gy in 35 fractions over 7 weeks (65 patients) or continuous hyperfractionated accelerated radiation therapy (V-CHART; 62 patients) or continuous hyperfractionated accelerated radiation therapy with 20 mg/sqm MMC on day 5 (V-CHART + MMC; 61 patients). By the accelerated regimens, the total dose of 55.3 Gy was delivered within 17 consecutive days, by 33 fractions. On day 1, a single dose of 2.5 Gy was given, from day 2 to 17 a dose of 1.65 Gy was delivered twice: the interfraction interval was 6 hours or more. RESULTS: Mucositis was very intense after accelerated therapy, most patients experiencing a grade III/IV reaction. The mucosal reaction did not differ whether MMC was administered or not. Patients treated by accelerated fractionation experienced a confluent mucosal reaction 12-14 days following start of therapy and recovered (no reaction) within 6 weeks. The skin reaction was not considered different in the three treatment groups. Those patients treated with additional chemotherapy experienced a grade III/IV hematologic toxicity in 12/61 patients. Initial complete response (CR) was recorded in 43% following CF, 58% after V-CHART, and 67% after V-CHART + MMC, respectively (p < 0.05). Actuarial survival (Kaplan-Meier) was significantly improved in the combined treated patients. Local tumor control was 28%, 32%, and 56% following CF, V-CHART, and V-CHART + MMC, respectively (p < 0.05). CONCLUSION: We conclude that our continuous hyperfractionated accelerated radiation therapy regimen is equal to conventional fractionation, suggesting that by shortening the overall treatment time from 7 weeks to 17 days a reduction in dose from 70 Gy to 55.3 Gy is possible, with maintenance of local tumor control rates. The administration of MMC to the accelerated regimen is tolerable and improves the outcome for patients significantly.     

Differential activation of right superior parietal cortex and intraparietal sulcus by spatial and nonspatial attention

Malignant brain tumors (primary and metastatic) are apparently resistant to most therapeutic efforts. Several randomized trials have provided evidence supporting the efficacy of radiation therapy. Attempts at improving the results of external beam radiotherapy include altered fractionation, radiation sensitizers and concomitant chemotherapy. In low-grade gliomas, all clinical studies with radiotherapy have employed conventional dose fractionation regimens. In high-grade gliomas, hypofractionation schedules represent effective palliative regimens in poor prognosis subsets of patients; short-term survival in these patients has not allowed to evaluate late toxicity. In tumors arising within the central nervous system, hyperfractionated irradiation exploits the differences in repair capacity between tumour and late responding normal tissues. It may allow for higher total dose and may result in increased tumor cell kill. Accelerated radiotherapy may reduce the repopulation of tumor cells between fractions. It may potentially improve tumor control for a given dose level, provided that there is no increase in late normal tissue injury. In supratentorial malignant gliomas, superiority of accelerated hyperfractionated over conventionally fractionated schedules was observed in a randomized trial; however, the gain in survival was less than 6 months. At present no other randomized trial supports the preferential choice for altered fractionation irradiation. Also in pediatric brainstem tumors there are no data to confirm the routine use of hyperfractionated irradiation, and significant late sequelae have been reported in the few long-term survivors. Shorter treatment courses with accelerated hyperfractionated radiotherapy may represent a useful alternative to conventional irradiation for the palliation of brain metastases. Different considerations have been proposed to explain this gap between theory and clinical data. Patients included in dose/effect studies are not stratified by prognostic factors and other treatment-related parameters. This observation precludes any definite conclusion about the relative role of conventional and of altered fractionation. New approaches are currently in progress. More prolonged radiation treatments, up to higher total doses, could delay time to tumor progression and improve survival in good prognosis subsets of patients; altered fractionation may be an effective therapeutic tool to achieve this goal.     

Treatment of patients with malignant neoplasms of the nose and paranasal sinuses

The author analyzes and discusses characteristic features of the results of combined treatment in 260 patients with malignant tumours of the superior maxilla, nose and accessory sinuses. The majority of patients were from 40 to 60 years old (81.5%). These were 158 men and 102 women. Epithelial tumours were diagnosed in 91.5%, sarcomas in 8.5% cases. The flattened-cell form of cancer with or without keratosis was diagnosed in 82.7%; other forms of cancer-in 17.3% cases. Sarcoma in women was diagnosed 3.5 times as often as in men. Tumours of the I stage were found in 12, of the II stage in 34. of the III stage in 146, of the IV stage in 73 patients. All patients were subjected to combined treatment-telegammatherapy and resection of the tumour with an electroknife. Patients with cancer of the I stage were first operated on with the electroknife and then subjected to radiotherapy with a focal dose of 3000-4000 rad. The 34 patients with cancer of the II stage underwent preoperative radiotherapy with a focal dose of 4500 to 5000 rad, then surgical intervention followed in 2-5 weeks. Preoperative radiotherapy was practiced in the 146 patients with cancer of the III stage, the total dose per focus being 5000-6000 rad, surgical intervention followed in 3-5 weeks. The 73 patients with cancer of the IV stage were operated on after radiotherapy with a focal dose of 6500-700 rad. Early and remote results of combined treatment in 260 patients were favourable. The length of life was up to 3 years in 119 (45.77%), up to 5 years in 74 (28.46%), up to 10 years in 48 (18.5%), over 10 years in 22 (8.5%) patients.     

Fluorine-18-fluoro-L-DOPA dosimetry with carbidopa pretreatment

This article presents dosimetry based on the measurement of fluoro-DOPA activity in major tissues and in the bladder contents in humans after oral pretreatment with 100 mg carbidopa. METHODS: Bladder activity was measured continuously by external probe and calibrated using complete urine collections. Quantitative dynamic PET scans provided time-activity curves for the major organs. Bladder wall dosimetry was calculated using the methods of MIRD Pamphlet No. 14. Effective dose was calculated as described in ICRP Publication 60. RESULTS: Mean absorbed dose to the bladder wall surface per unit administered activity was 0.150 mGy/MBq (0.556 rad/mCi) with the realistic void schedule used in our studies. The dose was 0.027 mGy/MBq (0.101 rad/mCi) to the kidneys, 0.0197 mGy/MBq (0.0728 rad/mCi) to the pancreas, and 0.0186 mGy/MBq (0.0688 rad/mCi) to the uterus. Absorbed doses to other organs were an order of magnitude or more lower than the bladder, 0.009-0.015 mGy/MBq. The effective dose per unit administered activity was 0.0199 mSv/MBq (0.0735 rem/mCi.) CONCLUSION: Urinary excretion of fluoro-DOPA was altered significantly by pretreatment with carbidopa. In general, any manipulation of tracer metabolism in the body should be expected to produce changes in biodistribution and dosimetry. The largest radiation dose was to the bladder wall, for which our estimate was one-fifth of that from the original report. The methods used reflect realistic urinary physiology and typical use of this tracer. The principles of MIRD Pamphlet No. 14 should be used in planning studies using tracers excreted in the urine to minimize the absorbed dose.     

Results of radiotherapy of malignant testicular neoplasms

It is very difficult to compare the therapeutic results of malignant testicular tumours because of the different histological classification systems, the uncertainty in the definition of the different stages, the error rate of the lymphography which amounts up to 35%, and the multitude of surgical, radiation, and chemotherapeutic methods. A histological classification and an exact determination of the stage is required as a condition of beginning a radiotherapy. The desirable focal dose for seminomas is between 4000 and 5000 rad, the maximum dose for teratomas is 6000 rad. For the stages T1-3N0 the iliac and the paraaortic lymph nodes are irradiated, for the stages T1-4N1-2 the interpleural space andthe supraclavicular region are included. For a group of 91 patients there was reached a five-year survival rate of 85,5% in case of seminomas and of 64% in case of teratomas.     

Radiotherapy for post-operative inflammatory breast cancer

Two patients with inflammatory breast cancer treated with a combination of radical mastectomy, irradiation, and immunochemotherapy are reported. After radical mastectomy, both patients were given a dose of 4000 rad and 5000 rad to the chest wall and parasternal lymph nodes, and 5000 rad to the axillary and supraclavicular lymph nodes. However, both patients died of recurrence within the irradiated field of the chest wall and metastatic spread to the neighbouring skin. A discussion on the dose and field in radiation therapy for inflammatory breast cancer is presented.     

Human biodistribution and dosimetry of the PET perfusion agent copper-62-PTSM

Copper-62-pyruvaldehyde bis(N4-methyl)thiosemicarbazone (PTSM) has been proposed as a generator-produced radiopharmaceutical for perfusion imaging using PET. Several clinical studies have demonstrated the ability of 62Cu-PTSM to quantitate myocardial and cerebral perfusion in humans. Because 62Cu-PTSM is generator-produced, it can be provided to clinical centers without cyclotron availability and, therefore, represents a cost-effective, practical PET perfusion tracer for clinical applications. To assess the safety, time-dependent biodistribution, and whole-body and organ-specific absorbed radiation dose estimates of this tracer, a Phase I study of 62Cu-PTSM was performed using whole-body imaging with PET in 10 healthy volunteers and with the radiopharmaceutical delivered by a compact modular generator unit. METHODS: Five male and five female subjects underwent a series of clinical tests and head-to-midthigh, whole-body PET scans at three time points over 1 hr after intravenous injection of 62Cu-PTSM. Before injection of the tracer, PET transmission scans were performed and used to correct the emission data for attenuation. Final image data were expressed in units of mCi/cc. Using standard organ weights, the percent injected dose per organ was calculated. Biodistribution data were obtained at three different time points and from these data biological half-lives in different organs were determined for calculation of radiation absorbed dose estimates. RESULTS: The liver was seen as the critical organ receiving a dose of 0.0886 rad/mCi. This organ defined the maximum single injected dose at 56 mCi using the limit of 5 rads to a critical organ per study per year. The whole-body dose is 0.0111 rad/mCi, resulting in a 0.622 rad exposure with a maximum single injection dose. Only trace levels of activity were found in the urine, which suggests low levels of urinary excretion and bladder exposure. No significant clinical, electrocardiographic or laboratory abnormalities were seen after the injection of 62Cu-PTSM. CONCLUSION: Copper-62-PTSM is a clinically safe radiopharmaceutical with favorable dosimetry for human studies at injected doses significantly above those projected for use in clinical studies.     

Scattered radiation doses to infants and children during EMI head scans

Scattered radiation doses to the eyes, thyroid and gonads of infants and children undergoing EMI head scans have been measured with thermoluminescent dosimeters. An average skin dose of 1.3 rad per scan was measured. Results are reported relative to incident skin dose and indicate that it is likely that there is no somatic or genetic hazard due to scattered radiation during an EMI head scan.     

The Nicolas Andry Award-1995. Fracture healing. Radiation induced alterations

This study investigated the effects of radiation on fractures in a rat femur model. Two different radiation dosage fractionation schemes (1100 rads given in one dose and 2500 rads given in 10 divided doses over 12 days) and three different times of initiation of radiation (1 day before fracture, 3 or 10 days after fracture) were studied. Fractures exposed to these levels of radiation all appeared to heal during the course of this experiment, although with varying degrees of delay, with the exception of those exposed to a single dose of 1100 rads 3 days after fracture. These animals remained at a more immature level of repair histologically compared with the control group, throughout the entire time evaluated. The strength of the final repair remained less than the control for all the groups receiving treatment. These results may offer some explanation for the clinical observations of an increased incidence of delayed union and nonunion of fractures, an increased incidence of fracture and refracture in irradiated bone, and an increased incidence of fracture and nonunion in constructs using radiation in conjunction with allogeneic bone. Furthermore, the observed effects were generally no different in the animals treated with the two clinically relevant dose fractionation schemes chosen for this study.     

Radiotherapy of plantar heel spurs: indications, technique, clinical results at different dose concepts

BACKGROUND: In a retrospective study the efficacy of orthovoltage radiotherapy for refractory painful plantar heel spur was analyzed for 3 different radiation dose concepts. PATIENTS AND METHODS: From 1.1 1984 through 1.3.1994, 182 patients with refractory painful heel symptoms and radiologically proven plantar heel spur received radiotherapy. A total of 141 patients and 170 heels (due to double-sided symptoms) were completely documented in long-term follow-up. Clearly defined semi-quantitative criteria (9-point score) were used to analyze heel pain and ankle function prior to RT, 6 to 12 weeks post-radiation, and at last follow-up. The treatment outcome, i.e. (un)favourable response, of 3 radiation dose concepts were compared: Group A (n = 72 heels) received 12 Gy total radiation dose in 3 fractions per week and 2 series (6 x 1 Gy per series) separated by 6 weeks; group B (n = 98 heels) received 3 Gy total radiation dose in 10 fractions of 0.3 Gy (n = 50) or 5 Gy (10 x 0.5 Gy) (n = 48) with conventional fractionation in 1 series. RESULTS: Radiotherapy was very effective: at last follow-up 67% (group A) and 71% (group B) remained completely free of pain. The rate of "complete pain relief" (i.e. free of any pain symptoms) was not different between the 3 radiation concepts. However, significant differences were observed with regard to "incomplete or insufficient pain relief", i.e. a subjective pain relief of less than 80%, a delayed pain relief after more than 4 weeks or a relapse of pain symptoms in long-term follow-up. More favourable results were achieved in patients receiving 5 Gy or 12 Gy total dose, while patients with 3 Gy total dose had significantly worse results. Prognostic factors for "complete pain relief" were short duration of pain symptoms and acute pain symptoms prior to radiotherapy; with regard to "in-complete or insufficient pain relief" the total dose was found to be a prognostic parameter. CONCLUSIONS: Patients with refractory heel pain can yield a high response to radiotherapy even after failing various conventional treatments previously. Thus, radiotherapy should not be solely regarded as a last resort due to its low costs and high efficacy at low radiation doses.     

Pharmacokinetic modeling and absorbed dose estimation for chimeric anti-CEA antibody in humans

The objective of this article was to model pharmacokinetic data from clinical diagnostic studies involving the 111In-labeled monoclonal antibody (MAb) chimeric T84.66, against carcinoembryonic antigen. Model-derived results based on the 111In-MAb blood, urine and digital imaging data were used to predict 90Y-MAb absorbed radiation doses and to guide treatment planning for future therapy trials. Fifteen patients with at least one carcinoembryonic antigen-positive lesion were evaluated. We report the kinetic parameter estimates and absorbed 111In-MAb dose and projected 90Y-MAb doses for each patient as well as describe our approach and rationale for modeling an extensive set of pharmacokinetic data. METHODS: The ADAPT II software package was used to create three- and five-compartment models of uptake against time in the patient population. The "best-fit" model was identified using ordinary least squares. Areas under the curve were calculated using the modeled curves and input into MIRDOSE3 to estimate absorbed radiation doses for each patient. RESULTS: A five-compartment model best described the liver, whole body, blood and urine data for a subcohort of nine patients with digital imaging data. A three-compartment model best described the blood and urine data for all 15 clinical patients accrued in the clinical trial. For the subcohort, the largest projected 90Y-MAb doses were delivered to the liver (mean, 24.78 rad/mCi; range, 15.02-37.07 rad/mCi), with red marrow estimates on the order of 3.32 rad/mCi (range, 1.24-5.55) of 90Y. Corresponding estimates for the 111In-MAb were 3.18 (range, 2.09-4.43) and 0.55 (range, 0.34-0.74), respectively. CONCLUSION: The three- and five-compartment models presented here were successfully used to represent the blood, urine and imaging data. This was evidenced by the small standard errors for the kinetic parameter estimates and R2 values close to 1. As planned future therapeutic trials will involve stem cell support to alleviate hematological toxicities, the development of an approach for estimating doses to other major organs is crucial.