Acute toxicities and cumulative dose to the brain of repeated sessions of stereotactic radiotherapy (SRT) for brain metastases: a retrospective study of 184 patients.

BACKGROUND: Stereotactic radiation therapy (SRT) is a focal treatment for brain metastases (BMs); thus, 20 to 40% of patients will require salvage treatment after an initial SRT session, either because of local or distant failure. SRT is not exempt from acute toxicity, and the acute toxicities of repeated SRT are not well known. The objective of this study was to analyze the acute toxicities of repeated courses of SRT and to determine whether repeated SRT could lead to cumulative brain doses equivalent to those of whole-brain radiotherapy (WBRT). MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs via two to six SRT sessions for local or distant BM recurrence without previous or intercurrent WBRT were retrospectively reviewed. Patients were seen via consultations during SRT, and the delivered dose, the use of corticosteroid therapy and neurological symptoms were recorded and rated according to the CTCAEv4. The dosimetric characteristics of 79% of BMs were collected, and summation plans of 76.6% of BMs were created. RESULTS: 36% of patients developed acute toxicity during at least one session. No grade three or four toxicity was registered, and grade one or two cephalalgy was the most frequently reported symptom. There was no significant difference in the occurrence of acute toxicity between consecutive SRT sessions. In the multivariate analysis, acute toxicity was associated with the use of corticosteroid therapy before irradiation (OR = 2.6; p = 0.01), BMV grade (high vs. low grade OR = 5.17; p = 0.02), and number of SRT sessions (3 SRT vs. 2 SRT: OR = 2.64; p = 0.01). The median volume equivalent to the WBRT dose (VWBRT) was 47.9 ml. In the multivariate analysis, the VWBRT was significantly associated with the total GTV (p < 0.001) and number of BMs (p < 0.001). Even for patients treated for more than ten cumulated BMs, the median BED to the brain was very low compared to the dose delivered during WBRT. CONCLUSION: Repeated SRT for local or distant recurrent BM is well tolerated, without grade three or four toxicity, and does not cause more acute neurological toxicity with repeated SRT sessions. Moreover, even for patients treated for more than ten BMs, the VWBRT is low.

Changes in the characteristics of patients treated for brain metastases with repeat stereotactic radiotherapy (SRT): a retrospective study of 184 patients.

PURPOSE: Brain metastases (BMs) are the leading cause of intracranial malignant neoplasms in adults. WHO, Karnofsky performance status (KPS), age, number of BMs, extracerebral progression (ECP), recursive partitioning analysis (RPA), diagnosis-specific graded prognostic assessment (Ds-GPA) are validated prognostic tools to help clinicians decide on treatment. No consensus exists for repeat stereotactic radiotherapy (SRT) for BMs. The aim of this study was to review the changes in patient characteristics treated with repeated SRTs. METHODS AND MATERIALS: The data of patients treated between 2010 and 2020 with at least two courses of SRT without previous whole brain radiotherapy (WBRT) were reviewed. Age, WHO, KPS, ECP, type of systemic treatment, number of BMs were recorded. RPA, Ds-GPA and brain metastasis velocity (BMV) were calculated. RESULTS: 184 patients were treated for 915 BMs and received two to six SRTs for local or distant brain recurrence. The median number of BMs treated per SRT was 1 (range: 1-6), for a median of 4 BMs treated during all sessions (range: 2-19). WHO, Ds-GPA and RPA were stable between each session of SRT, whereas KPS was significantly better in SRT1 than in the following SRT. The number of BMs was not significantly different between each SRT, but there was a tendency for more BM at SRT1 (p = 0.06). At SRT1, patients had largest BM and undergo more surgery than during the following SRT (p < 0.001). 6.5%, 37.5% and 56% of patients were classified as high, intermediate, and low BMV, respectively, at the last SRT session. There was almost perfect concordance between the BMV-grade calculated at the last SRT session and at SRT2 (r = 0.89; p < 0.001). CONCLUSION: Repeated SRT doesn't lead to a marked alteration in the general condition, KPS was maintained at over 70% for more than 95% of patients during all SRTs. Long survival can be expected, especially in low-grade BMV patients. WBRT shouldn't be aborted, especially for patients developing more than twelve BMs annually.

Radionecrosis after repeated courses of radiotherapy under stereotactic conditions for brain metastases: Analysis of clinical and dosimetric data from a retrospective cohort of 184 patients.

PURPOSE: Between 10 and 40% of patients with cancer will develop one or more brain metastases (BMs). Stereotactic radiotherapy (SRT) is part of the therapeutic arsenal for the treatment of de novo or recurrent BM. Its main interest is to delay whole brain radiation therapy (WBRT), which may cause cognitive toxicity. However, SRT is not exempt from long-term toxicity, and the most widely known SRT is radionecrosis (RN). The objective of this study was to analyze the occurrence of RN per BM and per patient. MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs by two to six SRT sessions for local or distant brain recurrence without previous or intercurrent WBRT were retrospectively reviewed. RN was examined on trimestral follow-up MRI and potentially confirmed by surgery or nuclear medicine. For each BM and SRT session plan, summation V12Gy, V14Gy, V21Gy and V23Gy isodoses were collected. Volumes of intersections were created between the 12Gy isodose at the first SRT and the 18Gy isodose of the following SRT (V18-12Gy). RESULTS: At the end of follow-up, 23.0% of patients presented RN, and 6.3% of BM presented RN. Median follow-up of BM was 13.3 months (95%CI 18.3-20.8). The median interval between BM irradiation and RN was 8.7 months (95% CI 9.2-14.7). Six-, 12- and 24-month RN-free survival rates per BM were 75%, 54% and 29%, respectively. The median RN-free survival per patient was 15.3 months (95% CI 13.6-18.1). In multivariate analysis, the occurrence of RN per BM was statistically associated with local reirradiation (P<0.001) and the number of SRTs (P<0.001). In univariate analysis, the occurrence of RN per patient was statistically associated with the sum of all V18-12Gy (P=0.02). No statistical association was found in multivariate analysis. A sum of all V18-12Gy of less than 1.5ml was associated with a 14.6% risk of RN, compared with 35.6% when the sum of all V18-12Gy was superior to 1.5ml. The sum of all V18-12Gy larger than 1.5ml was associated with a 74% specificity and 53% sensitivity of RN (P<0.001). CONCLUSION: Based on these results, a small number of BMs show RN during repeated SRT for local or distant recurrent BMs. Local reirradiation was the most predictive factor of brain RN. A V18-12Gy larger than 7.6ml in the case of local reirradiation or larger than 1.5ml in proximity reirradiation were prognostic factors of RN. The more BM patients need radiation therapy, and the longer they survive after irradiation, the higher their individual risk of developing RN.

[Prognostic factors of acute radiodermatitis in breast cancer after adjuvant radiotherapy treated with RT3D or IMRT]. / Étude des facteurs pronostiques de radiodermite aiguë dans le cancer du sein traité par irradiation conformationnelle adjuvante avec ou sans modulation d'intensité.

PURPOSE: Real life study of prognostic factors of acute radiodermatitis in a monocentric cohort of 200 patients with breast cancer treated with RT3D or IMRT for adjuvant radiotherapy. PATIENTS AND METHODS: This study comprises 200 patients with breast cancer treated with adjuvant radiotherapy, included consecutively. For each patient, their clinical and tumoral characteristics and the irradiation schedule was retrospectively collected. The severity of acute radiodermatitis was also collected, during the treatment and 6weeks after the end of irradiation. The objective was to identify risk factors for acute radiodermatitis grade≥2. RESULTS: The univariate analysis found that a more important BMI (p<0.001), a more important volume of PTV (p<0.001) a normofractionated schedule (p=0.002) were statistically associated to a greater risk of occurrence of grade≥2 acute radiodermatitis. The multivariate analysis found BMI>30 (OR=9.31, p=0.04), light phototype (OR=0.04, p=0.02) and histology other than invasive breast carcinomas (OR=0.07, p=0.04) to be statistically associated to the occurrence of grade≥2 acute radiodermatitis. CONCLUSION: In this monocentric retrospective study, with a prospective collection of the severity of acute radiodermatitis, no grade 3 radiodermatitis has been observed and the frequency of occurrence of grade 2 radiodermatitis was lower than previously published. In contrast to previously published results, IMRT was not associated to a lower risk of grade≥2 acute radiodermatitis. Multivariate analysis found BMI, phototype, and histology to be risk factors of grade≥2 acute radiodermatitis.

Management of metallic implants in radiotherapy.

The number of patients with metallic implant and treated with radiotherapy is constantly increasing. These hardware are responsible for the deterioration in the quality of the CT images used at each stage of the radiation therapy, during delineation, dosimetry and dose delivery. We present the update of the recommendations of the French society of oncological radiotherapy on the pros and cons of the different methods, existing and under evaluation, which limit the impact of metallic implants on the quality and safety of radiation treatments.

[Impact of thoracic irradiation on cardiac structures]. / Impact de la radiothérapie thoracique sur les structures cardiaques.

Thoracic irradiation requires protection of the heart as an organ at risk of complications. The mean heart dose is the most studied dosimetric parameter in the literature. Recent studies question its relevance in view of the multiplicity of cardiac injuries, the heterogeneity of the cardiac dose distribution and the current technical possibilities to refine cardiac dosimetric protection. The objective of this literature review is to analyze the available scientific data on the impact of the dose received by the cardiac substructures. A search of articles using the PubMed search engine was used to select the most relevant studies. A total of 19 articles were selected according to pre-established criteria to answer the issue. Several studies found significant associations between dosimetric parameters of substructures and clinical cardiological impact. Some proposed dose constraints for substructures.

Delineation of organs at risk.

The delineation of organs at risk is the basis of radiotherapy oncologists' work. Indeed, the knowledge of this delineation enables to better identify the target volumes and to optimize dose distribution, involving the prognosis of the patients but also their future. The learning of this delineation must continue throughout the clinician's career. Some contour changes have appeared with better imaging, some volumes are now required due to development of knowledge of side effects. In addition, the increasing survival time of patients requires to be more systematic and precise in the delineations, both to avoid complications until now exceptional but also because re-irradiations are becoming more and more frequent. We present the update of the recommendations of the French Society for Radiation Oncology (SFRO) on new findings or adaptations to volumes at risk.

[Overall survival and survival without local recurrence in case of radiotherapy of the tumor bed of ductal carcinomas in situ of the breast: Review of the literature]. / Survie globale et sans récidive locale en cas de radiothérapie du lit tumoral des carcinomes canalaires in situ du sein : revue de la littérature.

INTRODUCTION: Carcinomas in situ represent more than 15 to 20% of breast cancers. Radiotherapy of whole breast is part of the therapeutic standard and follows surgery. However, the indication of tumor bed irradiation is still controversial and heterogeneous according to international practice even though it is a very frequent clinical situation. The aim of this study is to define the indications of tumor bed irradiation in the context of ductal carcinomas in situ and to discuss accelerated partial irradiation of the breast. METHOD: The selected papers were published between 2015 and 2020 and included as MeSH terms "ductal carcinoma in situ" and "boost" for the analysis of tumor bed irradiation, and "ductal carcinoma in situ" and "accelerated partial breast irradiation" for the analysis of accelerated partial irradiation. RESULTS: Boost was more often performed when risk factors for local recurrence were present, such as age less than 40 or 50 years old, clinical mode of detection, tumor size greater than 15 to 20mm, high nuclear grade, presence of necrosis, positive or insufficient surgical margins, associated atypical hyperplastic lesions, and lobular carcinoma in situ. Accelerated partial irradiation is an option for favorable or intermediate prognosis CCIS, further studies involving more patients are required. CONCLUSION: Radiotherapy of the mammary gland in the context of DCIS has shown its effectiveness in terms of local and locoregional control of the disease, thus reducing in situ and infiltrating recurrences. However, the indication of operating bed irradiation is still debated, and the practice is very heterogeneous depending on the country. Another possible alternative for patients with a favorable prognosis and a small tumor bed volume would be IPA.

[What is the place of surgery in the management of brain metastases in 2020?] / Quelle est la place de la chirurgie dans la prise en charge des métastases cérébrales en 2020 ?

Brain metastases are the most common intracranial tumors and are associated with a dismal prognosis. The management of patients with brain metastases has become more important because of the increased incidence of these tumours, the better treatment of the systemic disease and the improvement of surgical techniques. The treatment requires multidisciplinary approaches and become complex because of new emerging systemic therapy and advancements in neurosurgery and radiation oncology. The surgical treatment has an indispensable role to obtain a tissue diagnosis, in relieving intracranial effect mass and improving neurological status by improving induced encephalopathy. An understanding of the role and indications of the surgery in patients with metastatic brain lesions is essential for the effective management of this growing population.

[Cost of radiotherapy for bone metastases in France: A monocentric retrospective study]. / Coût de la radiothérapie des métastases osseuses en France : étude rétrospective monocentrique.

PURPOSE: The cost of radiotherapy is a concern for health systems. The conventional non fractionated or multifractionated schemes have shown the same efficacy in terms of pain relief but a non fractionated treatment seems less expensive. However, in general practice, multifractionated treatments are still the majority, which represents an additional cost for society. Moreover, the use of stereotactic body radiotherapy becomes more democratic and offers new curative perspectives, but at what price? MATERIAL AND METHODS: A monocentric retrospective study was conducted in a French radiotherapy department to evaluate and compare the cost of irradiation of uncomplicated bone metastases according to the selected radiotherapy regimen : 30Gy in 10 fractions, 20Gy in five fractions, 8Gy in one fraction or stereotactic body radiotherapy. RESULTS: Between January 2014 and December 2015, 91 patients receiving 116 treatments were included in the study, including 44 men (48%) and 47 women (52%) were 63 years old (25-88 years). Thirty-four treatments (29%) were performed by 30Gy in 10 fractions (30Gy group), 24 treatments (21%) by 20Gy in 5 fractions (20Gy group), 25 treatments (22%) by 8Gy in one fraction (8Gy group) and 33 treatments (28%) by stereotactic body radiotherapy (SBRT group). The cost of stereotactic body radiotherapy was significantly higher than that of three-dimensional treatments (P<0.001). If the cost of transport was added to this cost, stereotactic body radiotherapy remained the most expensive (P<0.001). The cost of the irradiation delivering 30Gy treatment was significantly higher than the cost of treatment with 20Gy (P=0.006) or 8Gy (P<0.001), even after adding the transport cost (P<0.001), with no significant difference between 20Gy and 8Gy (P=0.11). For the overall cost of treatment including the total cost of treatments, associated transport and reirradiation, stereotactic body radiotherapy was the most expensive treatment (P<0.001) and this cost was significantly higher in the 30Gy group than in the 20Gy group (P=0.012) or 8Gy group (P=0.001), with no significant difference between 20Gy and 8Gy (P=0.38). There was no significant difference in the cost of follow-up between 30Gy, 20Gy, 8Gy and stereotactic body radiotherapy at one month (P=0.09) but at three months (P=0.01) and six months (P=0.0001), this cost was significantly higher after a three-dimensional treatment. There was no significant difference in overall cost including initial radiotherapy, transport and overall follow-up over 6 months between groups (P=0.04). CONCLUSION: Stereotactic body radiotherapy is an efficient and curative irradiation technique but more expensive. It is preferred for some patients with a longer life expectancy in a non-palliative treatment setting. The treatment delivering 8Gy treatment appears to be the most cost-effective while leading to an equivalent efficiency to multifractionated treatments and preserving the quality of life of patients.

[Radiation-induced lung toxicity predictors after stereotactic radiation therapy for non-small cell lung carcinoma stage I]. / Facteurs prédictifs de toxicité pulmonaire après irradiation en conditions stéréotaxiques des carcinomes bronchopulmonaires non à petites cellules de stade I.

In case of refusal or contraindication for surgical management of a stage I non-small cell lung carcinoma, the validated alternative therapy is stereotactic irradiation. This technique reaches an equivalent tumour control rate than surgery and significantly higher than conventional radiotherapy. One of the dreaded complications is radiation induced lung toxicity (radiation pneumonitis and lung fibrosis), especially when it is symptomatic, occurring in about 10 % of cases. This article is a literature review of this complication's predictive factors.

[Bone metastases radiotherapy: Multi-approaches literature review]. / Radiothérapie des métastases osseuses : revue multi-approches de la littérature.

External beam radiation therapy is an efficient treatment, which relieves pain associated with bone metastases, and is prescribed in worldwide. Although bone metastases palliative irradiation recommendations exist, international clinical practices remain variable. The purpose of this article is to show the clinical practices evolution though clinical trials, cost studies and techniques' progression.

[Radiotherapy of bone metastases in France: A descriptive monocentric retrospective study]. / Radiothérapie des métastases osseuses en France : étude descriptive rétrospective monocentrique.

PURPOSE: Bone metastases cause pain and affect patients' quality of life. Radiation therapy is one of the reference analgesic treatments. The objective of this study was to compare the current practices of a French radiotherapy department for the treatment of uncomplicated bone metastases with data from the literature in order to improve and optimize the management of patients. MATERIAL AND METHODS: A retrospective monocentric study of patients who underwent palliative irradiation of uncomplicated bone metastases was performed. RESULTS: Ninety-one patients had 116 treatments of uncomplicated bone metastases between January 2014 and December 2015, including 44 men (48%) and 47 women (52%) with an average age of 63years (25-88years). Primary tumours most commonly found were breast cancer (35%), lung cancer (16%) and prostate cancer (12%). The regimens used were in 29% of cases 30Gy in ten fractions (group 30Gy), in 21% of cases 20Gy in five fractions (group 20Gy), in 22% of cases 8Gy in one fraction (group 8Gy) and in 28% of cases 23.31Gy in three fractions of stereotactic body irradiation (stereotactic group). The general condition of the patient (P<0.001), pain score and analgesic (P<0.001), oligometastatic profile (P=0.003) and practitioner experience (P<0.001) were factors influencing the choice of the regimen irradiation. Age (P=0.46), sex (P=0.14), anticancer treatments (P=0.56), concomitant hospitalization (P=0.14) and the distance between the radiotherapy centre and home (P=0.87) did not influence the decision significantly. A total of three cases of spinal compression and one case of post-therapeutic fracture were observed, occurring between one and 128days and 577days after irradiation, respectively. Eight percent of all irradiated metastases were reirradiated with a delay ranging between 13 and 434days after the first irradiation. The re-irradiation rate was significantly higher after 8Gy (P=0.02). The rate of death was significantly lower in the stereotactic arm (P<0.001) and overall survival was significantly greater in the stereotactic arm (P<0.001). CONCLUSION: This study showed that patients' analysed was comparable to the population of different studies. Predictive factors for the choice of the treatment regimen were identified. Non-fractionnated therapy was underutilised while stereotactic treatment was increasingly prescribed, showing an evolution in the management of patients.

Metastatic mediastinal mature teratoma with malignant transformation in a young man with an adenocarcinoma in a Klinefelter's syndrome: Case report and review of the literature.

Malignant transformation of mediastinal mature teratoma is extremely rare and worsens the prognosis of the disease. Transformation can appear synchronously to or several years after the initial diagnosis. Clinical and radiological signs can orientate the clinician but the definitive diagnosis is obtained thanks to histology. An 11 year-old boy presented with a mediastinal mature teratoma and bone and pulmonary metastases. He received six cycles of chemotherapy combining etoposide, ifosfamide, cisplatin, followed by resection of a 16×14×9cm mediastinal mass. Karyotype analysis revealed the presence of an additional sex chromosome X (47 XXY) pathognomonic of Klinefelter's syndrome. Ten years later, sciatalgia revealed malignant transformation of a pre-existing sacral bone metastasis into gastrointestinal adenocarcinoma. The patient received four cycles of chemotherapy combining oxaliplatin, 5-fluorouracil and cetuximab. This treatment was followed by a complete resection of the sacral metastasis and completed with adjuvant irradiation of 54Gy in 30 daily fractions. Twelve months after the diagnosis of relapse, the patient remained alive without disease. To our knowledge, this is the first case of adenocarcinoma developed in bone metastases of a mediastinal mature teratoma in a boy with a Klinefelter's syndrome. We propose a review of the literature and an analysis of 20 others published cases of mediastinal teratoma with malignant transformation into adenocarcinoma.

[Big data, generalities and integration in radiotherapy]. / Les big data, généralités et intégration en radiothérapie.

The many advances in data collection computing systems (data collection, database, storage), diagnostic and therapeutic possibilities are responsible for an increase and a diversification of available data. Big data offers the capacities, in the field of health, to accelerate the discoveries and to optimize the management of patients by combining a large volume of data and the creation of therapeutic models. In radiotherapy, the development of big data is attractive because data are very numerous et heterogeneous (demographics, radiomics, genomics, radiogenomics, etc.). The expectation would be to predict the effectiveness and tolerance of radiation therapy. With these new concepts, still at the preliminary stage, it is possible to create a personalized medicine which is always more secure and reliable.

[Consequences of prosthesis on quality of the radiation therapy]. / Implications de la pose de matériel « inerte ¼ dans l'organisme humain sur la qualité de la radiothérapie.

Dose prescription, delineation and dose calculation are clearly complicated when a patient have been operated on with insertion of prosthesis. Knowledge of the physical and material characteristics is needed to decrease incertitude of calculations. Recommendations for each step of treatments are proposed in this article allowing to optimization of the treatment safety.

[Malignant intracerebral nerve sheath tumours: Two case reports and complete review of the literature cases]. / Tumeurs malignes des gaines nerveuses périphériques intracérébrales métastatiques: à propos de deux cas et revue exhaustive des cas de la littérature.

Malignant peripheral nerve sheath tumours are extremely rare and can be associated with neurofibramatosis type 1. Their prognosis is poor and surgery remains the mainstay of therapy and should be the first line of treatment. Radiotherapy and chemotherapy are second line treatment and their effectiveness remains to demonstrate. The diagnosis is clinical, radiological, histological and immunohistochemical. Malignant peripheral nerve sheath tumours have a potential of local tumour recurrence very high and can metastasize. They often occur in extremity of the members but also rarely into brain. We report two cases of intracerebral nerve sheath tumour. The first was a 68-year-old woman who was admitted with progressive symptoms of headache and diplopia. A left frontotemporal malignant peripheral nerve sheath tumours was diagnosed and was treated by surgery and irradiation. Ten months later, she presented a local recurrence and spine bone's metastases were treated by vertebroplasty and irradiation. The patient died 15 months after the diagnosis. The second case was a 47-year-old woman who was referred because headache and vomiting symptoms. A right frontal malignant peripheral nerve sheath tumours was diagnosed and treated by surgery and irradiation. After that, the patient had three local recurrence operated and pulmonary and cranial bone's metastases. She was still alive after 20 months. We propose a literature review with 25 cases of intracerebral nerve sheath tumour identified, including the two current cases.

[Luxation-fractures of the radiocarpal joint. Clinical study of 6 cases and general review]. / Luxation-fractures de la radio-carpienne. Etude clinique de six cas et revue générale.

The authors present a series of six cases of radio-carpal fracture-dislocation, which occurred between 1978 and 1989. The results were analysed with a follow-up of between 3 months and 11 years. This rare lesion (0.2% of all joint dislocations) is often caused by a severe injury, although the mechanism remains obscure. Radiological lesions consist of a combination of anterior or posterior carpal dislocation, fractures of the radial styloid and ulnar styloid processes, fracture of the anterior or posterior lip of the radius. This association of radiological lesion was also found in review of literature so that radio-carpal fracture-dislocation can be considered to be a real and a distinct entity. The authors recommend a surgical treatment, after immediate joint reduction, including stabilization with cancellous screw, sometimes Kirschner wires. However, anatomic reduction must be obtained, to ensure a good functional result.

Alterations of myc, myb, and rasHa proto-oncogenes in cancers are frequent and show clinical correlation.

Alterations of c-myc, c-rasHa, or c-myb oncogenes were found in more than one-third of human solid tumors. Amplification of c-myc occurred in advanced, widespread tumors or in aggressive primary tumors. Apparent allelic deletions of c-rasHa and c-myb can be correlated with progression and metastasis of carcinomas and sarcomas.

Human alpha-lymphoblastoid interferon. A phase I study including pharmacokinetics and effects on hematologic stem cells (CFU-GMs).

Human alpha lymphoblastoid interferon (Wellferon) was administered to 33 patients in a phase I study. Patients received Wellferon intramuscularly every 12 hours for 14 doses in nine dosage levels ranging from 0.75 X 10(6) units to 50.0 X 10(6) units. Toxicity tended to be dose dependent and included fever/chills, malaise, hematologic toxicity, and digestive tract toxicity. Thirty X 10(6) u q 12 h was felt to be the maximum tolerated dose. Three partial responses (renal cell carcinoma, diffuse histiocytic lymphoma, Hodgkin's disease) were achieved. Interferon rapidly (2 to 3 hours after the initial injection) reached peak serum levels which varied generally with dose and exceeded 500 u/ml at the 30 and 50 X 10(6) u dosages. Multiple doses of interferon resulted in cumulative peak levels substantially higher than first dose levels (greater than 500 u/ml at dosages greater than 3 X 10(6) u/ml and greater than 1,500 u/ml at dosages greater than or equal to 18 X 10(6) u). Interferon given at high dosages persisted up to 10 days beyond the final injection. Despite hematologic toxicity, inhibition of CFU-GM was not seen.