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Objective: Prospective evaluation of tumor regression during external irradiation for head and neck squamous cell carcinomas and its association with long-term local control., Methods and Materials: Two hundred twenty-eight patients with histologically confirmed squamous cell carcinoma [oral cavity: 59 (26%), oropharynx: 65 (29%), hypopharynx: 37 (16%), larynx: 67 (29%)] were included between January 1986 and December 1990. Curative intent external irradiation delivered 65-70 Gy over a period of 7 weeks (five 2 Gy fractions per week). Tumor regression was evaluated clinically and endoscopically every week., Results: Tumor regression, assessed at 2 weeks, was as follows: no response: 62 (30%), 25% response: 121 (59%); 50% response: 23 (11%). At 5 weeks, 9 (4%) patients showed 0-25% regression, 75 (33%) showed 50% regression, 115 (50%) showed 75% regression, and 29 (13%) showed complete regression. Median follow-up was 79 months (range: 6-96 months). The local control probability was 68% (62-74%) at 2 years, 65% (59-70%) at 5 years. Univariate analysis showed that, at 2 weeks, local control was significantly different between the nonresponders and the patients with 25% or greater response (p < 0.025) and that, at the fifth week, local control was very different between the major responders (75 and 100%) and the minor responders (0-50%) (p < 0.0001). Multivariate analysis (Cox Proportional Hazards Model) showed that the probability of local relapse was significantly and independently increased for minor regression at 5 weeks [Relative risk (RR) of failure was 2.3 (1.4-3.7)], for nonlaryngeal tumors [RR: 2.4 (1.3-4.5)], and for Stage T3-T4 [RR:2.4 (1.4-4)]. Three prognostic groups can, therefore, be proposed: 1) low risk of recurrence when regression > or = 75% and laryngeal tumor or T1-T2 tumors in other sites: 106 (46.5%) patients, 2-year local control probability: 84% (77-92%); 2) high risk of recurrence: regression < or = 50% and T3-T4 nonlaryngeal tumors: 44 (19%) patients, 2-year local control probability: 27% (13-41%); 3) intermediate risk of recurrence: 78 (34.5%) patients, 2-year local control probability: 69% (58-80%)., Conclusion: The present study suggests that tumor regression during external radiotherapy is an independent predictive factor of local control in head and neck carcinomas.

Purpose: to estimate the alpha/beta ratio for damage to human lung after thoracic irradiation for Hodgkin's disease., Patients and Methods: The criterion for lung injury was the presence of radiological changes in the vicinity of the mediastinum as assessed on regular follow-up chest X-ray examinations. Patients with supradiaphragmatic stage I-II Hodgkin's disease received mantle field irradiation as part of their treatment between 1964 and 1981 (E.O.R.T.C. protocols H1, H2, and H5). The total mediastinal doses fixed by the protocols were 35-40 Gy. The fractional doses were left to the decision of the physicians in charge: the most frequent regimens were 5 x 1.8, 5 x 2.0, 4 x 2.5 and 3 x 3.3 Gy per week. The data were fit to the linear-quadratic (L.Q.) model using time-to-injury as endpoint., Results: 1048 (97%) of 1082 patients were evaluable. The mean follow-up duration was 8 years. One hundred and ninety-five cases of radiologically-visible lung damage were observed after a median interval of 6 months (range: 0-101). The 3-year actuarial probability of lung damage was 19% (95% confidence limits: 17, 21). Multivariate analysis (Cox model, stratified by protocol) showed an increased risk of damage with dose per fraction (relative risk, R.R. = 2.22 per Gy (1.75, 2.82)), the presence of systemic symptoms (R.R. = 1.53 (1.09, 2.15)), and total mediastinal dose (R.R. = 1.06 per Gy (1.01, 1.12)). Age, sex, histological type, number of involved nodal sites and radiotherapy duration did not significantly modify the risk of lung damage. The L.Q. model parameters were: alpha = 0.031 Gy-1 (0.003, 0.059), beta = 0.010 Gy-2 (0.007, 0.013), alpha/beta = 3.07 Gy (-0.23, 8.46)., Conclusion: this low alpha/beta ratio is consistent with late effects values from animals and humans, and illustrates the influence of large fraction sizes on the occurrence of late pulmonary complications.

We report the results of a phase I study investigating the feasibility of concomitant daily doses of Carboplatin (20 to 25 mg/m2/d over 45 or 10 minutes) and accelerated chest irradiation (60 to 64 Gy over 4 weeks, 2 Gy per fraction, using the concomitant boost technique), alone or following three cycles of induction chemotherapy (cisplatin: 25 mg/m2 per day, d1 to d5, 5-Fluorouracil (5-Fu): 600 mg/m2 per day, d1 to d5, and Vinorelbine: 25 mg/m2 per day, d1 and d5, at 4-week intervals) in 15 patients with locally advanced unresectable nonsmall cell lung cancer. All patients received the planned sequence. The dose-limiting toxicity was esophagitis (5/15 WHO grade 4). No toxic deaths were observed. The tumor response rate was high: 6/15 complete responses and 8/15 greater than 50% tumor regressions. The median survival has not been reached after a mean follow-up of 14 months (range: 6, 28). We are now planning a multicenter phase II study, using the following doses: 20 mg/m2 of daily Carboplatin over 10 minutes and 60 Gy of radiotherapy over 4 weeks.

Two types of "severe accidental irradiation" can be schematically described: high dose localized irradiations and accidental total body overexposure. Actually, these two pathologies may coexist, and may be associated with external or internal radioactive contamination, and with all the "catastrophe medicine" syndromes. For high dose localized irradiation, physicians must manage as well as possible complex surgical procedures which unfortunately cannot always avoid being mutilating. For total body overexposure, haematological problems are at the forefront. In according with various situations, hematological growth factors or even allogeneic bone marrow transplantation will be discussed in specialized haematology (and transplant) units. The optimal management of severe accidental irradiation victims implies a close--and rapidly organized--cooperation between general practitioners, firemen, intensive care units, radiopathologists, specialist surgeons (hand and burns) and haematologists.

Medical radiation includes radiodiagnosis, nuclear medicine, and radiation therapy. This radiation exposure differs from occupational public exposure, since a direct benefit is conferred upon the patient. The theoretical risks include genetic mutations, carcinogenesis and teratogenesis. In radiodiagnosis and nuclear medicine, the absorbed doses are very low, and no hazardous effect has been observed. In radiation therapy however, where high doses are delivered to a small number of patients, radio-induced carcinogenesis is well documented. It is by no means sure that the nuclear risk must be taken into account, and fully justifies the accomplishments and recommendations of the French radiation protection programs. There is no question that the nuclear risk-benefit equation resulting from medical exposure is tipped heavily in favor of benefit.

Since the discovery of x-rays and radioactivity, the radiotherapeutic management of malignancy has seen numerous spectacular improvements. Beside the widely used photons and electrons, one area of particular interest is the development and refinement of what has become known as "new particles". In this paper we give a brief outline of the properties of such particles and catalogue the impact these have made on the clinical outcome.

Proton therapy offers potentially considerable advantages in the management of slow-growing, poorly resectable or non-resectable tumors resistant to x-rays and located close to critical radiosensitive anatomical structures, such as the brain stem of the spinal cord. Among over 13,000 irradiated patients in the USA, Europe, and Japan, two major clinical indications have been documented: 1. The conservative management of choroidal melanomas, in which 98% 5-year local control can be expected at the price of low toxicity and visual preservation in approximately half of them. 2. The curative management of low-grade chondrosarcomas and chordomas of the base of the skull and cervical spine, leading to, in combination with maximal tumor resection, 84%-94% long-term survival. Other ongoing studies concern prostate, head and neck carcinomas as well as various intracranial tumors. Radiosurgical programs are being conducted generally with single fractions and under stereotactic conditions.

Purpose: To evaluate the importance of fractionating total body irradiation (TBI) in patients receiving an allogenic bone marrow transplant (BMT) for an acute myeloblastic leukemia (AML) in first complete remission (CR1)., Methods and Materials: Between 1983 and 1990, 171 consecutive patients received either single dose TBI (STBI) (n = 65) or fractionated TBI (FTBI) (n = 106) after being conditioned with cyclophosphamide and before receiving a non-T-depleted Human Leucocyte Antigen (HLA)-identical marrow. Both groups were comparable except for date of BMT and diagnosis-to-BMT interval (D-BMT)., Results: After 63 months median follow-up, transplant-related mortality (TRM), probability of relapse, and 5-year disease-free survival (DFS) were 0.38 and 0.27 (p = 0.04), 0.29 and 0.26 (p = 0.22), 0.43 and 0.56 (p = 0.06), respectively, for STBI and FTBI. The supposed influence of the schedule of TBI disappeared in the multivariate analysis: TRM was enhanced by severe acute graft vs. host disease (p = 0.0002), early years of transplant (before January 1, 1987) (p = 0.0003), and longer D-BMT intervals (p = 0.038). Relapse was linked to early years of transplant (p < 0.00001), and the absence of chronic GVHD (p = 0.007). Longer DFSs were observed for later years of transplant (after January 1, 1987 and later) (p = 0.001), milder acute GVHD (p = 0.005), and shorter D-BMT intervals (p = 0.045). Important improvements of the results were made during the 7-year observation period: TRM, probability of relapse, and DFS were, respectively, 0.36, 0.28, and 0.46 for patients transplanted before January 1, 1987 vs. 0.21, 0.15, and 0.67 after that date., Conclusion: Our data strongly suggest that allogenic BMT is the best postremission treatment for AML in CR1, and the results are better when BMT shortly follows the achievement of remission. The schedule of TBI was of little importance compared with the improvements made in the management of patients undergoing BMT during the 1980s, and, therefore, reports concerning data prior to 1985 should be interpreted cautiously.

The potential doubling time (Tpot) is defined as the time necessary to double the number of proliferating tumor cells in the absence of spontaneous cell loss. Tpot is thought to be a better index of tumor proliferation than clinically observed tumour volume doubling time. The in vivo measurement of Tpot is a possible way to detect fast growing tumours which would be better controlled by accelerated radiotherapy. The published data demonstrate the feasibility and the safety of the technique. Large variations in Tpot values were observed in tumors with similar histology, indicating an accelerated proliferation rate in some tumors. There are technical difficulties related to intra-tumor heterogeneity, sample contamination by normal cells, and inter-laboratory variability, which question the biological interpretation of Tpot. Further studies are ongoing to establish whether the in vivo measurement of Tpot 1) provides information that is independent of the "classical" prognostic factors, and 2) allows the early recognition of the patients likely to benefit from accelerated treatment.

The present report concerns a retrospective study of 16 patients with localized intermediate- or high-grade non-Hodgkin's lymphoma of the testis treated in one institution from 1973 to 1990. Ann Arbor stage of disease was IE in 11 and IIE in 5 cases. All except one patient underwent initial inguinal orchidectomy, 11 were disease free after surgery and 12 received inverted Y radiation therapy. All patients achieved a complete remission (CR). Relapse occurred in 8 of 9 patients who did not receive initial chemotherapy, but in only 3 of 7 patients initially treated with chemotherapy including anthracyclins. In 3 cases relapse was confined to the CNS, while diffuse relapse in 8 others included 4 cases of CNS involvement. Eight patients are now alive in CR (5 in first CR, 1 in second CR and 2 in third CR) with a median follow-up of 68.5 months (range 54-101). Chemotherapy thus emerges as the initial treatment of preference for localized testicular lymphoma. Therapy should be preceded by a thorough assessment of the stage of disease and due to the high frequency of CNS relapse, CNS prophylaxis should be considered for all patients.

Purpose: To determine whether in vivo parameters (surviving fraction at 2 Gy, alpha values, and calculated cell growth fraction) were predictive of the treatment outcome., Methods and Materials: Biopsies were obtained from patients with a head and neck tumor. In vitro parameters were determined using the CAM plate assay. Cell characterization by cytogenetic analysis was performed on 19 different cell cultures. In 25 additional cell cultures, cell clonogenicity was tested using the Courtenay Mills assay., Results: Biopsies were obtained from 156 patients with a head and neck tumor and the oropharynx was the predominant primary site. In vitro parameters were obtained in 113 cases (72%) (SF2 in 93 cases and calculated cell growth fraction in 103 cases). Cell characterization showed that cells in CAM plates were diploid with no clonal chromosome abnormalities and gave colonies in soft agar with a mean cloning efficiency of 1.610(-3). Only patients treated with surgery and/or radiation (76), were considered eligible for in vitro parameters and treatment outcome correlation studies. The mean follow-up is over 2 years (range 9-47 months). The local control rate was significantly higher (p = 0.04) for patients with alpha values above the cut-off point of 0.07 Gy-1 (69% vs. 38% at 2 years). The local control rate was also significantly higher (p = 0.04) for patients with calculated cell growth fraction values about the cut-off point of 0.06% (70% vs. 48% at 2 years). Moreover for these latter patients the overall survival rate was also significantly higher (p = 0.004) (54% vs. 26% at 2 years). It is worth noting that alpha and calculated cell growth fraction values below the cut-off points identified a small group of patients (about 20%) who were at a significantly high risk of local failure. From a pragmatic point of view, as only radiosensitivity or calculated cell growth fraction values could be obtained in a certain number of experiments due to technical reasons, the treatment outcome of patients who had either alpha and/or calculated cell growth fraction values below the cut-off levels (about 30% of all patients) was analyzed. This group of patients fared significantly worse (p = 0.02) in terms of local control (50% vs. 68% at 2 years) and (p = 0.04) overall survival (36% vs. 50% at 2 years)., Conclusion: These results suggest that in vitro parameters using the CAM plate assay, might be useful in predicting the treatment outcome of patients with a head and neck tumor treated with surgery and postoperative radiation, or radiation alone. However, they must be considered as preliminary because the cut offs used in the study were chosen for exploratory purposes. Only a multivariate analysis including all clinical and biologic factors will allow us to draw any firm conclusions.

Purpose: To evaluate the incidence of lung complications and leukemia recurrences after two different doses to the lungs during total body irradiation., Methods and Materials: Seventy-nine patients with acute leukemia (AML or ALL) in first complete remission or chronic myeloid leukemia in the chronic phase, five patients with high grade lymphoma, and one with chronic lymphocytic leukemia were entered in the study. They were given a single dose of total body irradiation (10 Gy over 4 h) with two different doses to the lungs (6 Gy or 8 Gy) prior to bone marrow transplantation. The median dose rate was 0.04 Gy/min. The median follow-up for both groups of patients was 24 months., Results: The actuarial 5-year overall survival rate was similar in both groups, 59% and 43% for patients given 8 Gy and 6 Gy to the lungs, respectively. The lung complication rate was similar in the two groups (28% vs. 22% for the 8 Gy and 6 Gy group, respectively). The actuarial leukemia recurrence rate was significantly higher in the group of patients given 6 Gy to the lungs (25%) vs. 0% in the 8 Gy group. Interestingly, all recurrences occurred in the group of patients who were given 6 Gy to the lungs, who had acute leukemia, and no chronic graft vs. host disease (GVHD)., Conclusions: Although the number of patients was not very large and the follow-up relatively short, these findings suggest that a lower dose to the lungs could lead to an increased incidence of leukemia recurrences due to a lower dose to the thoracic wall or to lower incidence of chronic GVHD.

Purpose: This present review is intended to evaluate the specific influence of fractionation of total body irradiation on the outcome of a subsequent bone marrow transplantation., Methods and Materials: Available experimental and clinical data on the influence of fractionation on leukemia cell killing, immunosuppression, and sparing of normal tissues were analyzed., Results: Review of available data shows: (a) The role of fractionation on leukemia cell killing may vary with the leukemia type. For acute nonlymphoblastic leukemia, a few experimental and several clinical studies show no or little fractionation effect; a 12-13 Gy fractionated scheme could, therefore, be more efficient than a conventional 10 Gy single dose total body irradiation. For chronic myelogenous leukemia, some sensitivity to fractionation is suggested, so that an increase in total or fractional dose may be necessary in fractionated schemes to equate the efficacy of a 10 Gy single dose. For acute lymphoblastic leukemia, a high fractionation sensitivity was observed for some leukemic cell lines in vitro, without undisputable clinical confirmation for the moment. (b) Numerous experimental studies have demonstrated that the immunosuppressive effect of total body irradiation, a major determinant of engraftment, is highly fractionation sensitive. In humans, high rates of graft failures have been reported when T-cell depletion of the graft was associated to fractionated total body irradiation schedules. (c) A large amount of radiobiological and clinical data have demonstrated that late radiation-induced injuries to normal tissues and organs are highly fractionation sensitive. However, in a context of total body irradiation for bone marrow transplantation, the number of other determinants of normal tissue damage makes it difficult to demonstrate a clear-cut advantage of fractionated over single dose scheme, with a possible exception for children., Conclusions: In 1994, available data suggest that very cautious attempts could be made to adapt total body irradiation schedules to the potential normal tissue toxicity, T-cell depletion, and to the type of leukemia.

Total-body irradiation (TBI) induces an increase in levels of granulocytes and cortisol in blood. To explore the underlying mechanisms, we studied 26 patients who had TBI prior to bone marrow transplantation. Our findings suggest that only a high dose of TBI (10 Gy) was capable of activating the hypothalamo-pituitary area since corticotropin-releasing factor and blood adrenocorticotropic hormone levels increased at the end of the TBI. There was a concomitant increase in the levels of interleukin 6 and tumor necrosis factor in blood, suggesting that these cytokines might activate the hypothalamo-pituitary adrenal axis. Interleukin 1 was not detected. Since vascular injury is common after radiation treatment, it is possible that interleukin 6 was secreted by endothelial cells. The exact mechanisms of the production of cytokines induced by ionizing radiation remain to be determined.

Second primary cancers are a serious late occurrence for patients surviving Hodgkin's disease (HD). In addition to previously described risk factors such as age, gender, clinical stage, and treatment modalities, splenectomy was found to correlate with an increase in risk for secondary acute leukemia. We assumed that splenic irradiation inducing functional hyposplenia and splenectomy could have similar consequences on second cancer risk. We studied a series of 892 continuously disease-free HD adult patients treated at a single institution between 1960 and 1984. The risk of second cancer was analyzed (1) relative to the general population and (2) between risk subgroups using the Cox proportional hazards model. Fifty-six patients developed a second cancer (8 acute leukemias, 3 myelodysplastic syndromes, 8 non-Hodgkin's lymphomas, and 37 solid tumors; basal cell and in situ cervix carcinomas were excluded). The 15-year cumulative incidence rate (with 95% confidence limits) was 13.2% (9.3% to 17.2%). Relative to the general population incidence data, the risk of second cancer was multiplied by 4.68 (3.51 to 6.12; P < .001); it was multiplied by 2.80 (1.63 to 4.48; P < .001) in patients whose spleen was not treated and multiplied by 6.87 (4.81 to 9.51; P < .001) in splenectomized patients or patients whose spleen was irradiated. Multivariate regression analysis that controlled for confounding variables (age, gender, clinical stage, extent of radiation therapy, and chemotherapy regimen) showed that, in addition to age above 40 years (relative risk [RR] = 3.72; P < .001), combination of MOPP chemotherapy and regional irradiation (RR = 4.99; P = .015) and combination of MOPP chemotherapy and extended irradiation (RR = 10.86; P < .001), splenic irradiation (RR = 3.67; P = .003), and splenectomy (RR = 2.54; P = .018) also significantly correlated with an increased risk. The results of this hospital-based registry study strongly suggest that splenic irradiation and splenectomy might increase the risk for treatment-related second cancer. These findings, if confirmed, have to be considered in future HD treatment policies.

In 1994, late effects of radiotherapy should be limited to an acceptable rate of benign and non-disabling complications. In almost all cases, this goal can be presently reached, owe to recent technological and radiobiological advances. The precise adaptation of irradiated volume, dose, fractionation and total duration of treatment should avoid severe post-radiotherapeutic toxicity. The identification of subgroups of patients with high susceptibility to ionizing radiations should soon allow the radiotherapists to take up the challenge of a both efficient and non-toxic irradiation.

From December 1991 to September 1992, 20 patients due to receive total body irradiation (TBI) prior to allogenic or autologus bone marrow transplantation were given granisetron (Kytril) in order to prevent intestinal (nausea and vomiting) early intolerance. TBI regimen was delivered on a fractional basis of six fractions, over 3 days. Twelve grays were delivered with a lung protection decreasing the pulmonary dose to 9 Gy. Granisetron (3 mg) was administered by a 5-min intravenous infusion, 1 h before TBI. Up to two further infusions were given if nausea or vomiting occurred. The pretreatment perfusion was sufficient to prevent nausea and vomiting in 10/20 patients, one additional post-treatment perfusion was necessary in 7/20 patients, and two in 1/20 patients. In 2/20 cases, nausea and vomiting persisted in spite of three perfusions. Excellent or good efficacy was noted in 15/20 patients and a minor (or no) efficacy in five. Granisetron appears to be superior to the conventional anti emetic schemes to prevent nausea and vomiting in patients receiving TBI for bone marrow transplantation.

Purpose: We have evaluated irradiation doses received at location of secondary solid tumors occurring after bone marrow transplantation (BMT) in five of 147 patients grafted for severe aplastic anaemia., Results: All 5 tumors occurred within the radiation field penumbra. The estimated received dose varied from 6 Gy for one inner field secondary tumor, to 2.5 Gy for the remaining secondary tumors., Conclusion: Tumors may arise in the zone where the delivered radiation dose drops dramatically. Irradiation, with associated cofactors, may promote the development of epidermoid carcinoma in irradiated patients for BMT.

The purpose of this retrospective study was to evaluate the efficacy of low-dose limited field radiation therapy (LDLRT) in low-grade non-Hodgkin's lymphoma (NHL) patients, in order to outline its possible role. The rationale of the analysis was as follows: (1) there is no clear dose-response relationship for radiation therapy (RT) in localized low-grade non-Hodgkin's lymphomas (LGNHL); (2) long-term disease-free survival can be achieved in advanced LGNHL with low-dose (1.5-2 Gy) fractionated total body irradiation; (3) moreover, some of our previous LGNHL patients stopped their conventional planned RT course for convenience after 5 to 7.5 Gy and remained free from local progression in irradiated volumes for a long period of time. Patient selection criteria were the following: (1) patients with low-grade NHL (LGNHL); (2) patients who received no other form of therapy concomitantly with LDLRT until evaluation of the response; (3) patients who received a planned dose of 4 Gy in two fractions and over 3 days in a limited field. Out of 37 patients, 27 patients were fully evaluable. Twenty-two patients had stage III or IV disease. The median longevity of the disease was 73 months. Twenty-five patients had previously received chemotherapy (18 with anthracyclines). Nineteen patients had received one LDLRT course only. Eight patients responding to the first LDLRT had received at least one subsequent LDLRT course. After the first LDLRT course, an objective response in irradiated sites was observed in 24 of the 27 patients (89 per cent). Ten and 14 patients respectively demonstrated a complete response (CR) (37 per cent) and partial response (PR) (52 per cent). Freedom from progression in irradiated volumes for evaluable patients ranged from 4 to 35 months. Among the eight patients who received at least two LDLRT courses, a total of 20 different areas were irradiated, and 15 areas (75 per cent) showed a CR. Toxicity due to LDLRT was minimal. In conclusion, low-dose limited-field RT resulted in a high proportion of responses in LGNHL. The mechanisms explaining this radioresponsiveness are poorly understood. However, the efficacy of LDLRT could have several clinical applications in the general management of patients with advanced LGNHL.

The outcome of ovarian function preservation and fertility after ovarian transposition was examined in women treated for cancer. Of 134 patients, 126 were treated with radiotherapy and 72 with chemotherapy. In a multivariate analysis, three factors appeared to be prognostic of ovarian castration: the age over 25, MOPP chemotherapy and a total dose to the ovaries higher than 5 Gy. The incidence of birth was lower in the general population but no abnormality was observed.

Purpose: To determine whether in vitro radiosensitivity parameters are predictive of treatment outcome., Methods and Materials: Biopsies were obtained from patients with head and neck cancers (57) and cervical carcinomas (20) and in vitro radiosensitivity parameters were obtained using the CAM plate assay., Results: In most cases (75%) patients were treated with radiation alone. The median follow up was 461 days. When the whole group of head and neck cancers and cervical carcinomas was considered, patients with a SF2 value below 0.36 had a higher 2-year local control rate (93% versus 68%) and a higher 2-year survival rate (71% vs. 62%) than those with SF2 values above that threshold, but differences were not significant. These trends persisted when head and neck cancers were considered alone with a higher local control rate (86% vs. 67%) and a higher survival rate (75% vs. 52.5%) obtained for patients with a SF2 value below 0.36. When the alpha value was evaluated for the whole group of patients a significantly higher local control rate (80.5% vs. 40.5%) and overall survival rate (71% versus 37.5%) at 2 years were obtained for patients with alpha values above 0.07 Gy-1. When only the group of head and neck cancers was considered, local control rate was significantly higher (79% vs. 33%) but overall survival rate (65.5% vs. 33%) was not significantly higher for alpha values above 0.07 Gy-1., Conclusion: These results are encouraging but need to be confirmed with a larger number of patients with a longer follow-up.

Serum alpha-amylase was measured before and 24 h after either total body (31 patients) or localized irradiation including the salivary glands (40 patients) or the pancreatic area (22 patients). A significant increase in amylasemia was observed for doses to the parotid glands larger than 0.5 Gy. A sigmoid function of dose was fitted to the data and predicted a maximum amylasemia level for doses larger than 4 Gy and smaller than 10 Gy. The raw data from other published series were adequately described by the same model. However, the confidence limits of the parameters remained wide, because of a considerable interindividual variability. Post-irradiation hyperamylasemia appears to provide a good criterion for triage of accidentally irradiated patients: 24 h after a dose larger than 2 Gy to the parotid glands, 91% of the patients had an amylasemia level higher than 2.5-fold the upper normal value (sensitivity). Conversely, 96% had their serum amylasemia lower than 2.5-fold the upper normal value when dose was smaller than 2 Gy (specificity). However, a retrospective estimation of the absorbed dose (dosimetry) is not likely to be very precise because of the large interindividual variability.

Conflicting data have been reported on the incidence of myocardial abnormalities after mediastinal irradiation for Hodgkin's disease. We studied myocardial perfusion in 31 clinically asymptomatic patients (13 male, 18 female, mean age 35 years) 7 years (range 3-11 years) after mantle field radiotherapy. Thallium-201 tomoscintigraphic data were obtained after exercise, 4 h later and at rest (8-15 days later). Images were analysed visually and quantitatively (sectorial quantification of 201Tl uptake on the bull's eye images of the short-axis slices) compared with those of 35 subjects with a low likelihood of coronary artery disease. Twenty-five tomographic data sets were available. Images were visually abnormal in 21 patients (84%) showing an heterogeneous 201Tl uptake. In 68%, the sectorial 201Tl uptake was lower than the mean 201Tl uptake value minus 2 standard deviations measured in subjects with a low likelihood of coronary artery disease. Significant redistribution (quantitatively assessed > or = 10%) was present in 10 patients (40%). In most of the patients, the location and the shape of the defect(s) could not be anatomically related to an epicardial coronary vessel disease. These results indicate that after mediastinal irradiation the 201Tl myocardial uptake is frequently abnormal. The observed patterns suggest a disease of the small coronary vessels and/or the existence of a myocardial fibrosis rather than epicardial coronary artery disease.

Since 1980, 107 consecutive patients (pts) underwent bone marrow transplantation (BMT) for nonconstitutional severe aplastic anemia (SAA) at our institution. All received conditioning with Cytoxan (150 mg/kg) and thoraco-abdominal irradiation (6 Gy) from an HLA-identical sibling donor. Mean age was 19 years (5 to 46 years). Forty-nine pts had less than 0.2 x 10(9)/L PMN and 53 failed to respond to previous immunosuppressive therapy before BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate (22 pts), cyclosporine (52 pts), or both (33 pts). With a median follow-up of 45 months (12 to 120 months), overall actuarial survival was 68% (confidence interval 95%:9.7). Of 16 factors tested, five were shown to adversely influence survival by multivariate analysis: grade greater than or equal to 2 acute GVHD (relative risk [RR]: 5.5), prior immunosuppressive therapy (RR: 3.5), female as donor (RR: 2.4), nonidiopathic SAA (RR: 2), and more than 0.2 x 10(9)/L PMN AA (RR: 2). Because acute GVHD was the most potent factor for survival, we analysed risk factors for acute GVHD. By multivariate analysis, 2 of 14 factors tested were independent: male as recipient (RR: 3) and previous alloimmunization of the donor (RR: 4.3). On long-term follow-up, chronic GVHD was observed in 49 pts of 89 surviving more than 100 days (55%). Multivariate analysis showed that infection before transplant (RR: 1.3) and previous history of acute GVHD (RR: 1.8) were associated with an increased risk of chronic GVHD.

In 1991, the vast majority of radiotherapy centers are implemented with computer treatment planning systems (TPS), and it has become routine practice to compute full absorbed dose distribution (ADD) in almost all treatment situations. Usually the target is covered by the 100% isodose and the surrounding normal tissues receive a lesser dose than the tumor. It implies, that, as the dose per fraction of, say, 2 Gy is prescribed at the 100%, normal tissues receive a daily dose different than 2 Gy. The absorbed doses delivered at different organs have therefore not the same biological effectiveness and must be corrected according to the actual dose per fraction for a proper interpretation of the treatment planning. This is of great importance since most of the "tolerance levels" used in the practice have been determined for doses per fraction around 1.8-2 Gy. The linear-quadratic (LQ) model provides a simple method for establishing biological equivalencies and has been used throughout this article to establish the difference between the absorbed dose computed by the TPS and its biological equivalent. It is shown that normal tissues receiving less than 100% of the daily dose are relatively more protected than suggested by the ADD, and, inversely, that normal structures overdosed and thus receiving more than the 100% daily dose are relatively more at risk for complications than suggested from the ADD.

Tumor clonogenic cell content is believed to play an important role in the outcome of radiotherapy. However, there is no proven method to assess the number of clonogens in human tumors accurately. All currently available assays employ in vitro plating efficiency or in vivo TD50 (the average number of cells needed to induce tumors in 50% of injected mice) to estimate the tumor clonogenic ability. In this study, a monolayer mass primary culture system was used to estimate the clonogenic cell fraction in human tumors. For this purpose, 25 growth curves were performed for 25 tumor specimens derived from 21 head and neck and 4 cervical squamous cell carcinomas. The exponential portion of each growth curve was extrapolated through the ordinate (day 0) to estimate the clonogenic cell fraction; this method is only an estimate because it assumes no lag phase before exponential growth of clonogenic cells. The mean clonogenic cell fraction, expressed as clonogens/tumor cells inoculated, was relatively low (mean: 0.71%, range: 0.11-9.28), and the variation was wide (coefficient of variation = 148%). On the other hand, the doubling time of the growing population was 1.46 days and exhibited a very narrow range (0.98-2.24, coefficient of variation = 24%). The mean and range of clonogenic cell fraction were found to be in agreement with published values of soft agar colony forming efficiencies in both murine and human tumors. However, further investigation is necessary to determine how accurately this method measures the relative clonogenic cell content in human tumors. Clinical correlations between clonogenic cell fraction values and the response to radiotherapy are still too early to determine.

An analysis was performed of all 57 early relapses (ER) (within 18 months of therapy initiation) seen in a group of 301 patients treated on three successive European Organization for Research and Treatment of Cancer (EORTC) protocols from 1964 to 1981; to determine whether a posttherapy elevated erythrocyte sedimentation rate (ESR) (greater than or equal to 30 mm) could predict the type of relapse and the effect upon the relapse of different therapies received. Overall most ER occurred in extranodal (EN) (42%) or irradiated transdiaphragmatic nodal (TDN) (40%) sites. Compared to patients with normal posttherapy ESR (n = 12), patients with elevated posttherapy ESR (n = 45) had the same proportions of outfield and late relapses; more frequent multiple sites of ER (38% vs. 25%), increased proportions of early EN relapses (16% vs. 3%), TDN relapses (17% vs. 2%), and other ER (6% vs. 1%). ER were most frequently observed between 1964 and 1971, and "modern" radiotherapy (Rt) decreased ER overall from 27% to 13% and for elevated posttherapy ESR patients from 54% to 25%. When chemotherapy (Ct) was used as either adjuvant or initial therapy, ER were greatly reduced vs. Rt alone [overall (6% vs. 28%) and for patients with elevated posttherapy ESR (10% vs. 39%)]. Stepwise logistic regression showed Ct to be the most important factor "protecting" from EN relapse, but elevated posttherapy ESR was still significant. For early TDN relapse, elevated posttherapy ESR had the highest predictive value for relapse, greater than the types of radiation fields used and chemotherapy. An unexplained elevated posttherapy ESR, regardless of previous therapy, predicts for ER from aggressive HD, frequently in EN and irradiated areas, and warrants further early therapy.

From May 1980 to December 1989, 107 consecutive patients with non-constitutional severe aplastic anemia underwent bone marrow transplantation at our institution using cyclophosphamide and thoraco-abdominal irradiation as conditioning regimen. During the same period, 40 patients with Fanconi anemia were also grafted after a similar conditioning, giving a total series of 147 patients. With a mean follow-up of 64 months, four male patients developed a solid malignant tumor, a number that leads to an 8-year cumulative incidence rate of 22% (eg, relative risk to general population = 41, P less than .001). These results should be considered as a warning to clinicians who follow these successfully grafted long-term patients.

From 1971 to 1984, 499 patients with all stages of Hodgkin's disease received mediastinal irradiation at the Institut Gustave-Roussy by 25 MV photons from a linear accelerator. Thirty-five pericarditis (10-year cumulative incidence rate of 9.5%) and 13 myocardial infarctions (MI) (10-year cumulative incidence rate of 3.9%) were observed. In contrast, no cases were diagnosed in a parallel series of 138 Hodgkin's disease patients treated without mediastinal irradiation during the same period of time (p less than 0.005 for pericarditis, p less than 0.05 for MI). By multivariate analysis, the role of total radiation dose given to the mediastinum and that of fraction size were evaluated, adjusting for age, sex, mediastinal involvement, and type of chemotherapy. The pericarditis risk was significantly increased with total dose greater than or equal to 41 Gy (relative risk (RR) = 3.25, p = 0.006) and with dose per fraction greater than or equal to 3.0 Gy (RR = 2.0, p = 0.06). The myocardial infarction risk was not found to be related to total dose nor to fraction size in this series, possibly because of the small number of events.

Fractionated total body irradiation was given to a patient with chronic myeloid leukemia as part of a conditioning regimen for bone marrow transplantation. The radiation treatment was discontinued after the third fraction (total dose: 385 cGy) and no bone marrow graft was given because of the patient's refusal. Peripheral blood lymphocyte levels were monitored for 3 months and lymphocyte subsets up to 50 days post-irradiation. Lymphocyte numbers reached the nadir 48 h after the last fraction and lymphopenia was still present 3 months later. All lymphocyte subsets (T, B, CD4 and CD8 cells) showed a similar decrease except for natural killer cells which exhibited a larger decline. The regenerative capacity of T cells, CD4 subset and natural killer cells was less than that of B cells and CD8 lymphocyte subsets.

In 1980, based on experimental and clinical data, a protocol was developed at the Institut Gustave-Roussy (IGR), alternating eight monthly courses of chemotherapy (CHVP) and two, then three, radiotherapy sequences (15 Gy in 6 fractions and 10 days to the initially involved areas), for early stage unfavourable histology non-Hodgkin lymphomas (NHL). The results are updated for 55 selected patients presenting with bulky stage I and II NHL, intermediate and high grade according to the Working Formulation. Five-year overall survival rate was 69% and freedom from progression was 68%. Early haematologic and digestive tolerance was satisfactory, probably because a 10-15-day interval was respected between chemotherapy and radiotherapy and vice versa. No late toxicity was detected in 39 patients who presented with head and neck localizations; xerostomia was found to be only mild and transient. All patients given mediastinal irradiation experienced radiological mediastinitis, but functional impairment was usually moderate. One of the 4 patients who received 3 x 15 Gy radiotherapy courses to part of the abdomen, died of small bowel obstruction and perforation. The study demonstrated the feasibility of an alternated schedule of chemotherapy and radiotherapy, with satisfactory results in terms of long-term survival. However, the few late complications which were detected after irradiation of the abdomen or of the thorax led to an alteration of the initial scheme when these volumes are to be treated.