Early-stage mantle cell lymphoma: a retrospective analysis from the International Lymphoma Radiation Oncology Group (ILROG).

BACKGROUND: Mantle cell lymphoma (MCL) rarely presents as early-stage disease, but clinical observations suggest that patients who present with early-stage disease may have better outcomes than those with advanced-stage disease. PATIENTS AND METHODS: In this 13-institution study, we examined outcomes among 179 patients with early-stage (stage I or II) MCL in an attempt to identify prognostic factors that influence treatment selection and outcome. Variables examined included clinical characteristics, treatment modality, response to therapy, sites of failure, and survival. RESULTS: Patients were predominantly male (78%) with head and neck being the most common presenting sites (75%). Most failures occurred outside the original disease site (79%). Although the administration of radiation therapy, either alone or with chemotherapy, reduced the risk of local failure, it did not translate into an improved freedom from progression or overall survival (OS). The treatment outcomes were independent of treatment modality. The 10-year OS for patients treated with chemotherapy alone, chemo-radiation therapy and radiation therapy alone were 69%, 62%, and 74% (P = 0.79), and the 10-year freedom from progression were 46%, 43%, and 31% (P = 0.64), respectively. CONCLUSION: Given the excellent OS rates regardless of initial therapy in patients with early-stage MCL, de-intensified therapy to limit treatment-related toxicity is a reasonable approach.

Long-term survival among Hodgkin's lymphoma patients with gastrointestinal cancer: a population-based study.

BACKGROUND: The increased risk of gastrointestinal (GI) cancers after Hodgkin's lymphoma (HL) is well established. However, no large population-based study has described the actuarial survival after subsequent GI cancers in HL survivors (HL-GI). PATIENTS AND METHODS: For 209 patients with HL-GI cancers (105 colon, 35 stomach, 30 pancreas, 21 rectum, and 18 esophagus) and 484 165 patients with first primary GI cancers (GI-1), actuarial survival was compared, accounting for age, gender, race, GI cancer stage, radiation for HL, and other variables. RESULTS: Though survival of HL patients who developed localized stage colon cancer was similar to that of the GI-1 group, overall survival (OS) of HL patients with regional or distant stage colon cancer was reduced [hazard ratio, (HR)=1.46, P=0.01]. The HL survivors with regional or distant stage colon cancer in the transverse segment had an especially high risk of mortality (HR: 2.7, P=0.001 for OS). For localized stomach cancer, OS was inferior among HL survivors (HR=3.46, P=0.006). CONCLUSIONS: The HL patients who develop GI cancer experience significantly reduced survival compared with patients with a first primary GI cancer. Further research is needed to explain the inferior survival of HL patients and to define selection criteria for cancer screening in HL survivors.

Pediatric Normal Tissue Effects in the Clinic (PENTEC): An International Collaboration to Analyse Normal Tissue Radiation Dose-Volume Response Relationships for Paediatric Cancer Patients.

With advances in multimodality therapy, childhood cancer cure rates approach 80%. However, both radiotherapy and chemotherapy can cause debilitating or even fatal late adverse events that are critical to understand, mitigate or prevent. QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) identified radiation dose constraints for normal tissues in adults and pointed out the uncertainties in those constraints. The range of adverse events seen in children is different from that in adults, in part due to the vulnerability/characteristics of radiation damage to developing tissues, and in part due to the typical body sites affected by childhood cancer that lead to collateral irradiation of somewhat different normal tissues and organs compared with adults. Many childhood cancer survivors have a long life expectancy and may develop treatment-induced secondary cancers and severe organ/tissue injury 10, 20 or more years after treatment. Collaborative long-term observational studies and clinical research programmes for survivors of paediatric and adolescent cancer provide adverse event data for follow-up periods exceeding 40 years. Data analysis is challenging due to the interaction between therapeutic and developmental variables, the lack of radiation dose-volume data and the fact that most childhood malignancies are managed with combined modality therapy. PENTEC (Pediatric Normal Tissue Effects in the Clinic) is a volunteer research collaboration of more than 150 physicians, medical physicists, mathematical modellers and epidemiologists organised into 18 organ-specific working groups conducting a critical review and synthesis of quantitative data from existing studies aiming to: (1) establish quantitative, evidence-based dose/volume/risk guidelines to inform radiation treatment planning and, in turn, improve outcomes after radiation therapy for childhood cancers; (2) explore the most relevant risk factors for toxicity, including developmental status; (3) describe specific physics and dosimetric issues relevant to paediatric radiotherapy; and (4) propose dose-volume outcome reporting standards for publications on childhood cancer therapy outcomes. The impact of other critical modifiers of normal tissue radiation damage, including chemotherapy, surgery, stem cell transplantation and underlying genetic predispositions are also considered. The aims of the PENTEC reports are to provide clinicians with an analysis of the best available data to make informed decisions regarding radiation therapy normal organ dose constraints for planning childhood cancer treatment, and to define future research priorities.

Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer.

PURPOSE: Comprehensive cardiac evaluations are currently recommended for all anthracycline-treated patients to detect subclinical cardiac failure. A screening test is needed that would easily and inexpensively identify patients who are at risk for late cardiac decompensation. METHODS: We routinely reviewed the ECG and echocardiogram (ECHO) results of 52 of 56 anthracycline-treated long-term survivors of childhood cancer who had received > or = 100 mg/m2 of ANTH (ANTH = 1 mg/m2 of doxorubicin), and who were not in clinical heart failure. Exercise testing was performed in eight patients with a corrected QT interval (QTc) of > or = 0.43. RESULTS: Zero of 15 patients (without chest radiation) who received less than 300 mg/m2 of ANTH versus six of 22 who received > or = 300 mg/m2 of ANTH had a QTc > or = 0.43 (P = .03). Three of 15 patients (with chest radiation) who received less than 300 mg/m2 of ANTH versus 12 of 22 who received > or = 300 mg/m2 of ANTH had a QTc > or = 0.43 (P = .03). For all patients (including those with chest radiotherapy), zero of 19 who received less than 300 mg/m2 of ANTH versus eight of 33 who received > or = 300 mg/m2 of ANTH had a QTc of > or = 0.45 (P = .025). Three of 19 who received less than 300 mg/m2 of ANTH versus 19 of 33 who received > or = 300 mg/m2 of ANTH had a QTc of > or = 0.43 (P = .003). One patient had decreased fractional shortening (FS) and QTc prolongation. Cardiac decompensation (with a FS of 24%) occurred with propranolol in a patient with previously normal FS but prolonged QTc. With exercise, the QTc became further prolonged in all four patients with a QTc of 0.44 to 0.46 and in two of four patients with a QTc of 0.43. CONCLUSION: Prolongation of the QTc, a measure of myocardial repolarization, may reflect injury to myocardial cells. QTc prolongation may be predictive of an increased risk of late cardiac decompensation. If the utility of the QTc measure is confirmed, screening for evidence of myocardial damage can be easily and inexpensively performed by oncologists and primary caretakers.

Hyperprolactinemia and hypothyroidism following cytotoxic therapy for central nervous system malignancies.

Endocrinologic dysfunction including hyperprolactinemia and hypothyroidism are recognized complications of irradiation to the hypothalamic-pituitary axis or thyroid gland in the course of treating CNS malignancies. However, the frequency of these adverse effects in both short- and long-term survivors may be underestimated. Sixty-five patients treated in the University of Rochester Cancer Center since 1968 with radiation with or without BCNU chemotherapy for CNS tumors not involving the hypothalamic-pituitary axis were evaluated for thyroid, prolactin, and gonadal disturbances regardless of clinical symptomatology. Prolactin values were elevated in 19 of 47 patients (40%). For males and females treated with greater than 55 Gy, abnormal values were present in nine of 11 (82%) and seven of 14 (50%), respectively. For males and females treated with less than or equal to 55 Gy, two of nine (22%) and one of 13 (8%), respectively, were abnormal (P = .0001). Six of six patients who also received BCNU chemotherapy were hyperprolactinemic, as compared with six of ten (60%) who did not receive BCNU. Seven of eight females with elevated prolactin levels had menstruation abnormalities, and five of seven adult males noted a decrease in libido. Mild abnormalities in testosterone concentration were found in three of nine men evaluated, all of whom had normal gonadotropins. Of 47 patients who did not receive irradiation to the spinal axis (and thus the thyroid gland), ten (21%) had a decreased thyroxin (T4) value. Only one of these patients had an elevated thyroid-stimulating hormone (TSH) value. Of 32 patients who received greater than 55 Gy, ten (31%) had a low T4, compared with zero of 15 who received less than or equal to 55 Gy (P = .0001). Four of eight patients (50%) who also received BCNU had low T4 values, as compared with three of 14 (21%) who did not receive BCNU. Of 15 patients who were treated with 4 to 10 MV photon irradiation to the spinal axis, five patients (33%) had elevated TSH values. The mean spinal axis dose in these patients was 33 Gy. Two euthyroid children in this group manifested the early onset of puberty. The complex of endocrinologic abnormalities observed in several patients receiving only cranial irradiation, that is elevated prolactin, decreased thyroid, and gonadal hormone secretion in the presence of otherwise normal pituitary hormone levels, suggests a radiation-induced insult to the hypothalamic regulation of pituitary function.

Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by low-dose regional radiation in advanced Hodgkin's disease in children: a report from the Children's Cancer Study Group.

Sixty-four patients aged 2 to 18 years with advanced-stage Hodgkin's disease (HD) were treated on a Children's Cancer Study Group (CCSG) pilot toxicity study (521-P). Therapy consisted of 12 courses of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), bleomycin, vinblastine, and dacarbazine (ABVD), followed by low-dose (2,100 cGy in 12 fractions) regional irradiation (RT). All patients were monitored for toxicity with particular attention to the pulmonary system. Six patients (9%) developed grade 3 or 4 pulmonary toxicity. Three had grade 3 toxicity based solely on changes in carbon monoxide diffusing capacity (DLCO) and remained well for more than 3 years after diagnosis. There was one fatality among the three symptomatic cases. In five cases, toxicity occurred prior to RT. One occurred after seven courses of ABVD, one after nine courses, and three after 10 courses. In one of these five cases, ABVD was stopped. The patient was given nitrogen mustard (mechlorethamine), vincristine, prednisone, and procarbazine (MOPP). This patient subsequently developed recurrence of HD and died of overwhelming sepsis. The other four continued on study and completed their chemotherapy. Three patients had no further bleomycin, and one continued bleomycin at 50% of the assigned dose. They all received mantle RT following chemotherapy, one with a boost dose to the mediastinum to 3,800 cGy and one with added RT to both lungs (1,050 cGy). In the sixth case of pulmonary toxicity, symptoms were first noticed 2 weeks after mantle RT to 3,500 cGy. This patient died of progressive respiratory failure. The event-free survival (EFS) and overall survival is 87% at 3 years. These early results indicate that this therapy is effective in advanced HD in children but has a 9% incidence of acute pulmonary toxicity.

Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants.

PURPOSE: To identify predictors of oral mucositis and gastrointestinal toxicity after high-dose therapy. PATIENTS AND METHODS: Mucositis and gastrointestinal toxicity were prospectively evaluated in 202 recipients of high-dose therapy and autologous or allogeneic stem-cell rescue. Of 10 outcome variables, three were selected as end points: the peak value for the University of Nebraska Oral Assessment Score (MUCPEAK), the duration of parenteral nutritional support, and the peak daily output of diarrhea. Potential covariates included patient age, sex, diagnosis, treatment protocol, transplantation type, stem-cell source, and rate of neutrophil recovery. The three selected end points were also examined for correlation with blood infections and transplant-related mortality. RESULTS: A diagnosis of leukemia, use of total body irradiation, allogeneic transplantation, and delayed neutrophil recovery were associated with increased oral mucositis and longer parenteral nutritional support. No factors were associated with diarrhea. Also, moderate to severe oral mucositis (MUCPEAK > or = 18 on a scale of 8 to 24) was correlated with blood infections and transplant-related mortality: 60% of patients with MUCPEAK > or = 18 had positive blood cultures versus 30% of patients with MUCPEAK less than 18 (P =.001); 24% of patients with MUCPEAK > or = 8 died during the transplantation procedure versus 4% of patients with MUCPEAK less than 18 (P =.001). CONCLUSION: Gastrointestinal toxicity is a major cause of transplant-related morbidity and mortality, emphasizing the need for corrective strategies. The peak oral mucositis score and the duration of parenteral nutritional support are useful indices of gastrointestinal toxicity because these end points are correlated with clinically significant events, including blood infections and treatment-related mortality.

Chronic neuroendocrinological sequelae of radiation therapy.

A variety of neuroendocrine disturbances are observed following treatment with external radiation therapy when the hypothalamic-pituitary axis (HPA) is included in the treatment field. Radiation-induced abnormalities are generally dose dependent and may develop many years after irradiation. Growth hormone deficiency and premature sexual development can occur following doses as low as 18 Gy fractionated radiation and are the most common neuroendocrine problems noted in children. Deficiency of gonadotropins, thyroid stimulating hormone, and adrenocorticotropin are seen primarily in individuals treated with > 40 Gy HPA irradiation. Hyperprolactinemia can be seen following high-dose radiotherapy (> 40 Gy), especially among young women. Most neuroendocrine disturbances that develop as a result of HPA irradiation are treatable; patients at risk require long-term endocrine follow-up.

Sarcoma therapy: functional outcome and relationship to treatment parameters.

PURPOSE: To systematically assess the functional outcome of patients treated with surgery and irradiation for extremity or truncal sarcomas, and to correlate this outcome with a detailed analysis of the radiation dose distribution and surgical technique. Conservative surgery and radiation therapy (RT) are known to provide excellent local control, but the relationship of technique to functional outcome requires further study. METHODS AND MATERIALS: Forty-one patients were treated for lower extremity (25 patients, 61%), upper extremity (8 patients, 19.5%), and truncal (8, 19.5%) sarcomas from 1983 to 1990. Most patients had malignant fibrous histiocytoma (15), liposarcoma (8), or aggressive fibromatosis (6). Age ranged from 13 to 85 years (median 54). All patients received RT and 39 (95%) had surgery. The mean total RT dose was 59 Gy (range 55.8-64.8 Gy). A protocol for functional assessment was devised and included a 4 point scale (0-3) for each of seven functional parameters (range of motion, fibrosis, edema, pain, skin changes, muscle strength, gait, or upper extremity performance). An aggregate score was obtained by adding the seven parameter scores and compared with both a patient and physician overall functional rating score (excellent, good, fair, poor). Based on this analysis, aggregate scores were defined as < or = 3 = excellent, < or = 8 = good, < or = 13 = fair, and > 13 = poor, with 21 as the worst possible score. The same orthopaedic surgeon and radiation oncologist independently examined and rated 22 patients. An additional 17 patients were evaluated by record review. The median time from completion of radiation therapy was 30.5 months (range 7-95 months). A computerized radiation therapy dosimetric analysis was performed on 34 patients. RESULTS: Local control was achieved in 39 patients (95%), including 6 with aggressive fibromatosis. The mean functional outcome score was 5.1 with a range of 0-16. 34 patients (83%) had good or excellent functional outcomes. The rating system demonstrated minimal interobserver variability. There was a positive relationship between volume irradiated to > or = 55 Gy and functional score, strength, fibrosis, and skin changes. Total dose independent of volume was significantly associated with skin changes. Increasing peak dose (hot spot dose) was associated with fibrosis and skin changes. More fibrosis developed as the volume of the peak dose increased. A portion of the joint was treated in 5/33 extremity patients and the entire joint in 24/33 (mean dose 55.8 Gy, range 45-65 Gy). Neither range of motion nor total functional score was correlated with joint dose. Edema and functional score were not related to either the volume or percent of limb spared (receiving < or = 40 Gy). The physician functional status ratings generally concurred with patient self-assessments. CONCLUSIONS: A system for functional assessment has been developed which is easily performed and provides detailed information about patient functional outcome. This system can be used to evaluate the morbidity of combined modality sarcoma therapy. Doses up to 65 Gy, even over joint spaces, are not associated with significant morbidity. Only a small volume treated to < or = 40 Gy is required to maintain good outcome. The most important parameter appears to be the volume treated to > or = 55 Gy.

Protection by WR-2721 of human bone marrow function following irradiation.

Protection by WR-2721 of bone marrow (BM) from depression following hemibody irradiation (HBI) was assessed in patients receiving palliative therapy for widespread symptomatic metastasis on a Phase I/II Radiation Therapy Oncology Group (RTOG) protocol. Twenty-five patients are currently evaluable for the assessment of hematologic toxicity. HBI (600 or 700 cGy) was delivered starting 15-30 min after WR-2721 (600-900 mg/m2) intravenous infusion. Twenty patients from previous RTOG HBI studies were comparable in terms of radiation dose, hematologic data, and previous cytotoxic therapy. The WBC and platelet count nadirs at any time within 6 wk following HBI were used for data analysis, and toxicity was rated according to RTOG criteria. For the patients treated with WR-2721, moderate, severe, or life-threatening toxicity were seen in 16%, 12%, and 0% of the patients, respectively, compared to 30%, 15%, and 10% of patients in the group not treated with WR-2721. For the subpopulation of patients treated with the higher irradiation dose (700 cGy), differences in toxicity appeared to be greater. Conversely, for the sub-population of patients treated only to the upper hemibody, the difference in toxicity was less apparent. The percentage change from the median pre-treatment white blood cell (WBC) and platelet counts (PC) was not different between the WR-2721 treated and non-treated group; however, the median WBC count for the WR-2721 group returned to the pre-treatment value by the fourth week following HBI, whereas, it remained at 61% of the pre-HBI value for the control group. Within the group of patients treated with WR-2721, 5 of 17 (29%) receiving 600 mg/m2 demonstrated a greater than 75% decline in either WBC or platelets, compared to 0/8 patients treated with 750-900 mg/m2. These preliminary data support a protective effect by WR-2721 on radiation-induced bone marrow depression in humans, which may become more apparent with the use of higher radiation and WR-2721 doses.

Thyroid abnormalities after therapeutic external radiation.

The thyroid gland is the largest pure endocrine gland in the body and one of the organs most likely to produce clinically significant abnormalities after therapeutic external radiation. Radiation doses to the thyroid that exceed approximately 26 Gy frequently produce hypothyroidism, which may be clinically overt or subclinical, as manifested by increased serum thyrotropin and normal serum-free thyroxine concentrations. Pituitary or hypothalamic hypothyroidism may arise when the pituitary region receives doses exceeding 50 Gy with conventional, 1.8-2 Gy fractionation. Direct irradiation of the thyroid may increase the risk of Graves' disease or euthyroid Graves' ophthalmopathy. Silent thyroiditis, cystic degeneration, benign adenoma, and thyroid cancer have been observed after therapeutically relevant doses of external radiation. Direct or incidental thyroid irradiation increases the risk for well-differentiated, papillary, and follicular thyroid cancer from 15- to 53-fold. Thyroid cancer risk is highest following radiation at a young age, decreases with increasing age at treatment, and increases with follow-up duration. The potentially prolonged latent period between radiation exposure and the development of thyroid dysfunction, thyroid nodularity, and thyroid cancer means that individuals who have received neck or pituitary irradiation require careful, periodic clinical and laboratory evaluation to avoid excess morbidity.

Adverse effects of brain irradiation correlated with MR and CT imaging.

Forty-one patients treated for primary malignancies of the brain at the University of Rochester Cancer Center since 1970 were assessed for adverse effects of irradiation clinically, and by computerized tomography (CT) and magnetic resonance (MR) imaging. At diagnosis, patients ranged in age from 1-65 years (median 19 years) and the most common tumor (in 30) was astrocytoma. Radiation doses ranged from 45 to 81.3 Gy (median 56.8 Gy). White matter changes visible on MR were graded on a scale of 1-4, with grades 1-2 known to occur in some normal patients. Areas of increased signal intensity not associated with the tumor or surgery were visible in all patients (gr 1 = 37%, gr 2 = 32%, gr 3 = 17%, gr 4 = 15%) whereas only 35% had regions of abnormality (hypodensity) on CT. Sulci enlargement and ventricular abnormalities (asymmetry or dilatation) were present in approximately 50% of patients by each technique. Higher grade MR lesions were associated with radiation to large volumes and high doses. For the 36 patients treated with 1.5-2.0 Gy daily fractions, the mean radiation dose by grade was as follows: gr 1 = 55.1 Gy, gr 2 = 58.8 Gy, gr 3 = 60.0 Gy, gr 4 = 63.5 Gy. All 5 patients treated on a hyperfractionated schedule had gr 1-2 changes despite receiving greater than 70 Gy. Fifty percent of patients treated to the whole brain (+/- boost) had gr 3-4 changes, compared with 14% treated with local fields (peak dose regions similar in both groups). Among the children (less than or equal to 13 years), 20% had gr 3-4 changes compared with 56% of adults (excluding hyperfractionated patients). This finding may be due entirely or in part to the lower radiation doses used for children (mean 54.4 Gy vs. 63.7 Gy in adults). Clinical abnormalities attributable to irradiation included an impairment in mental functioning in 7 adults, and learning disabilities in 5 children. Five of these adults (71%) had gr 3-4 changes on MR as compared to gr 3-4 changes in 29% of the remaining adult group. Five patients developed seizure disorders. We conclude that adverse effects of brain irradiation are more sensitively imaged by MR than CT and that these abnormalities are associated with larger treatment volumes and either (or both) higher doses or older age. Conversely, some patients treated with high radiation doses have unremarkable changes on MR, and others have severe white matter changes which are not clinically expressed.(ABSTRACT TRUNCATED AT 400 WORDS)

Radiation effects on left ventricular function and myocardial perfusion in long term survivors of Hodgkin's disease.

We evaluated systolic and diastolic indices of left ventricular performance by radionuclide angiocardiography and myocardial perfusion with exercise/rest thallium scintigraphy in 16 patients previously irradiated for Hodgkin's disease. These commonly used indices of left ventricular (LV) performance included LV ejection fraction (LVEF) as a measure of systolic function, and LV peak filling rate (PFR) as a measure of diastolic function. The presence of coronary artery disease (CAD) was evaluated by ECG treadmill testing (13 patients) and by quantitative planar thallium scintigraphy (12 patients). Patients were 16-38 years old (mean 24.9 +/- SD 6.2) at the tim eof irradiation, and were evaluated 2.5-21.5 years (mean 9.3 +/- 6.3) after radiation therapy (RT). RT was delivered with beam energies of 2-18 MV, equally weighted AP-PA mantle fields with both fields treated daily for most patients (13 patients), and fraction sizes of 1.5-2.0 Gy. Six patients received radiation to th entire cardiac volume, most commonly via left-sided partial transmission lung blocks (PTLB). Patient data were analyzed according to the volume of heart treated. Individuals who had the entire cardiac volume irradiated were assigned to group I (N = 6), and those patients who had some portion of the heart shielded throughout treatment comprised group II (N = 10). In this series, no perfusion defects were evident in either group by quantitative planar thallium scintigraphy. Mean LVEF for all patients studied was 60% (normal LVEF greater than or equal to 50%). Patients in group I had a lower mean LVEF than those in group II, 55 +/- 4% versus 63 +/- 6% (p = 0.01). Mean PFR for all patients studied was normal at 3.5 EDV/sec (normal PFR greater than or equal to 2.54 EDV/sec). Patients in group I had a lower mean PFR than those in group II, 3.0 +/- 0.6 vs 3.8 +/- 0.7 EDV/sec (p = 0.04). Thus, patients irradiated to large cardiac and pulmonary volumes had lower LVEF and PFR within the normal range compared to patients who had some portion of the cardiac volume shielded. These differences are statistically significant in the relatively small groups studied but do not appear to be associated at the present time with clinically significant effects.

Interleukin 1 alpha stimulates hemopoiesis but not tumor cell proliferation and protects mice from lethal total body irradiation.

Interleukin 1 alpha (IL-1) is a polypeptide/glycoprotein growth factor with multiple functions including the modulation of hematopoietic cell proliferation and differentiation. In vivo studies were performed with C57BL/6J mice injected with 0, 0.2, or 2.0 micrograms of IL-1 24 hr before or after lethal total body irradiation (TBI) (9.5 Gy). More mice in the groups administered IL-1 before TBI survived (90% of the 2.0 micrograms group) than those treated 2 or 24 hr after TBI, which was still slightly superior to the uninjected group, which all died within 15 days (p = .0001). Proliferation of bone marrow granulocyte/macrophage colonies following split dose TBI was also greatest for mouse groups treated with IL-1 prior to TBI. These experiments support data from other investigators that IL-1 stimulation of BM is related to IL-1 timing with respect to TBI. Stimulation of hemopoiesis was also assessed in terms of changes in peripheral blood and BM cell numbers and cell cycle kinetics using an electronic particle counter and flow cytometric techniques. Mice injected with 2 micrograms of IL-1 showed an initial decline (at 3-6 hr) and then a selective proliferation (24-48 hr) of early and more committed progenitor cells to 125% and 200% of control values, respectively. Peripheral blood counts rose accordingly. Cells in S and G2/M phases increased over 10 hr and then declined in number. It thus appeared that some synchronization of cell cycling occurred, which might place cells in a more radioresistant phase of the cell cycle. The glutathione (GSH) content and synthesis in BM cells were measured by isocratic paired-ion high performance liquid chromatography and 35S-labelled cysteine incorporation into the GSH tripeptide. An increase in cellular GSH content and synthesis was demonstrated following IL-1 which lasted 24 hr, suggesting a possible mechanism for the radioprotection by IL-1. To determine the potential for achieving a favorable therapeutic ratio, KHT tumor-bearing mice were injected with 2.0 micrograms IL-1. No change in tumor diameters or weights or tumor cell clonogenicity between IL-1 treated or untreated animals was observed. These experiments strongly support a role for IL-1 in stimulating bone marrow to overcome the myelosuppressive effects of irradiation.

The development of an oral prodrug, SR-2545, of the 2-nitroimidazole radiosensitizer SR-2508.

SR-2508, a 2-nitroimidazole radiosensitizer, is expected to be clinically superior to desmethylmisonidazole or misonidazole because of its lower lipophilicity with subsequent lower drug levels in neural tissue and more rapid plasma elimination. The intravenous route of administration will be optimal but oral drugs may be necessary. Since decreased lipophilicity will decrease oral absorption we have synthesized, and tested in mice, SR-2545, an acetate ester prodrug of SR-2508. In the liver there is complete first pass metabolism to parent drug with no prodrug detectable in the blood. Compared to an equal dose of oral SR-2508, the prodrug yields a more rapid, reproducible, plasma peak with twice the bioavailability, peak plasma concentration and radiosensitization. If oral preparations of SR-2508 are to be used in the clinic the prodrug, SR-2545, is likely to be superior to oral SR-2508.

Radiation-induced changes in bone perfusion and angiogenesis.

PURPOSE: To determine whether blood flow of bone is altered by limb irradiation and whether bFGF, an angiogenic cytokine, might alleviate any flow or growth abnormality resulting from 30 Gy single fraction irradiation. METHODS AND MATERIALS: C3H mice received whole right hind limb radiation at doses of 0 to 30 Gy. Additional groups received 30 Gy, and then beginning 1 or 5 weeks later received intravenous bFGF at a dose of 6 microg/mouse, twice a week for 4 weeks. Serial X-ray films were taken to measure the tibias. At 33 weeks, laser Doppler flow (LDF) measurements were made of both limbs. Cytokine measurements were made using ELISA and RNase protection. RESULTS: Bone growth was reduced following radiation in a dose dependent manner. bFGF improved bone growth after radiation even when begun 5 weeks after radiation, however, we detected no significant improvement in LDF of the irradiated bone or periosteum. Muscle tissue surrounding bone of the irradiated leg showed no increase in isoforms of TGFbeta, TNF, or IFN. There was also no difference in the circulating plasma TGFbeta1 in irradiated mice. In contrast, LDF increased significantly as a function of radiation dose in the nonirradiated tibia. Systemic delivery of bFGF appears to further enhance the increase in flow seen in the nonirradiated limb. CONCLUSION: Radiation induces a chronic antiangiogenic effect contributing to reduced limb growth. At 33 weeks the antiangiogenesis was not associated with local soft tissue elevations of TNF, IFN, or TGFbeta. Radiation toxicity to bone is alleviated by bFGF therapy suggesting that powerful locally-acting antiangiogenic mechanisms are involved. We postulate that the increased LDF of the contralateral tibia is due to circulating angiogenesis factors that are elevated to compensate for the radiation-induced antiangiogenesis.