[en] Soft tissue sarcomas (STS) are malignant neoplasms arising from the mesenchymal connective and supporting tissues. These tumors occur at all anatomic sites within the body and are of many histologic subtypes. There are some 5600 newly diagnosed patients with STS per year. Epidemiological and etiologic factors, including the role of environmental carcinogens and radiation in the development of these tumors will be made. The role of several oncogenes and suppressor genes (e.g. Rb, p53, MDM2) and cytogenetic alterations will be reviewed. Consideration of the epidemiology and role of environmental carcinogens and radiation in the development of these tumors will be made. The natural history of these tumors will be described with reference to local invasion and spread to regional and distal sites. The evaluation of the patients suspected of having a sarcoma of soft tissue will then be considered including the relative roles of CT, MRI, PET, and US. The place of core needle biopsy, incisional biopsy or excisional biopsy for tumors at various sites and sizes will be addressed. The histopathologic subtype assessment of the tumor by standard H and E stains, immunohistochemistry, electron microscopy and cytogenetic studies will then be discussed. The principal role for radiation in the management of patients with sarcoma of soft tissue is in combination with surgery. This may be: 1) pre-operative and or post-operative use of external beam photons, electrons, and protons, and 2) intra-operative use of brachytherapy or intra-operative election beam techniques. Results of treatment with respect to local control, disease-free survival and overall survival will be considered for each of the various techniques with respect to size, grade, histologic type, surgical margin status, anatomic site, primary vs. recurrent disease. Similarly, the factors associated with delay in wound healing are to be considered and strategies to reduce wound morbidity. Functional outcome after limb-sparing procedures will be discussed. There are new accounts of impressive results of treatment with TNF and INF. Clinical and laboratory data are to be considered. Results of the several Phase III trials of adjuvant chemotherapy will be reviewed: trial design, patient numbers, implication for patient care. The role of radiation therapy in the management of a patient with sarcoma of soft tissue will be assessed with respect to radiation alone or in combination with surgery and/or chemotherapy or biological response modifiers. The radiation sensitivity measured in vitro for cells arising from sarcomas of soft tissue of human patients and experimental animals will be reviewed and compared with reference to clinical response patterns of epithelial tumors. Finally, there will be a brief coverage of the role of radiation in the treatment of several benign mesenchymal tumors, viz., desmoid tumors, atypical lipoma, fibrohistiocytoma, dermatofibrosarcoma protuberans, etc

[en] Soft tissue sarcomas (STS) are relatively rare malignant neoplasms arising from the mesenchymal connective tissues. There are some 5600 newly diagnosed patients with STS per year. These tumors occur at all anatomic sites within the body and are of many histologic subtypes. Etiologic factors, including occupational risks, the role of environmental carcinogens, radiation and genetic diseases in the development of these tumors will be made. The molecular biology of soft tissue sarcomas including the role of several oncogenes and suppressor genes (e.g. Rb, p53, MDM2) will be reviewed. Cytogenetic alternations with an emphasis on molecular diagnostic techniques will be reviewed. The natural history of these tumors will be described with reference to local invasion and spread to regional and distal sites. The evaluation of the patients suspected of having a sarcoma of soft tissue will then be considered including the relative roles of various imaging modalities. The timing and type of biopsy (including FNA, core needle biopsy, incisional biopsy or excisional biopsy) for tumors at various sites and sizes will be addressed. Assessment of histopathologic subtype of the tumor by standard H and E stains, immunohistochemistry, electron microscopy and cytogenetic studies will then be discussed. The principal role for radiation in the management of patients with sarcoma of soft tissue is in combination with surgery. This may be: 1) pre-operative and or post-operative use of external beam photons, electrons, and protons, and 2) intra-operative use of electron beam techniques, or 3) post-operative brachytherapy. Results of these various treatment options with respect to local control, disease-free survival and overall survival will be considered for each of the various techniques with respect to size, grade, histologic type, surgical margin status, anatomic site, primary vs. recurrent disease. Similarly, the factors associated with delay in wound healing are to be considered and strategies to reduce wound morbidity. Functional outcome after limb-sparing procedures will be discussed. There are new accounts of impressive results of treatment with perfusional TNF melphalan and interferon. The role of systemic chemotherapy in patients with M0 disease will be considered. Specifically, the results of the several Phase II and Phase III trials of adjuvant chemotherapy will be reviewed with respect to outcome; trial design, patient numbers, implication for patient care. The radiation sensitivity measured in vitro for cells arising from sarcomas of soft tissue of human patients and experimental animals will be reviewed and compared with reference to clinical response patterns of epithelial tumors. Finally, there will be a brief coverage of the role of radiation in the treatment of several benign mesenchymal tumors, including desmoid tumors and dermatofibrosarcoma protuberans

[en] Purpose/Objective: In a previous publication we reported that laboratory assays of tumor clonogen number, in combination with intrinsic radiosensitivity measured in-vitro, accurately predicted the rank-order of single fraction 50% tumor control doses, in six rodent and xenografted human tumors. In these studies, tumor hypoxia influenced the absolute value of the tumor control doses across tumor types, but not their rank-order. In the present study we hypothesize that determinants of the single fraction tumor control dose, may also strongly influence the fractionaled tumor control doses, and that knowledge of tumor clonogen number and their sensitivity to fractionated irradiation, may be useful for predicting the relative sensitivity of tumors treated by conventional fractionated irradiation. Methods/Materials: Five tumors of human origin were used for these studies. Special care was taken to ensure that all tumor control dose assays were performed over the same time frame, i.e., in-vitro cells of a similar passage were used to initiate tumor sources which were expanded and used in the 3rd or 4th generation. Thirty fraction tumor control doses were performed in air breathing mice, under normal blood flow conditions (two fractions/day). The results of these studies have been previously published. For studies under uniformly (clamp) hypoxic conditions, tumors arising from the same transplantation were randomized into single or fractionated dose protocols. For estimation of the fractionated TCD50 under hypoxic conditions, tumors were exposed to six 5.4 Gy fractions (∼ 2 Gy equivalent under air), followed by graded 'top-up' dose irradiation for determination of the TCD50; the time interval between doses was 6-9 hours. The single dose equivalent of the six 5.4 Gy doses was used to calculate an extrapolated 30 fraction hypoxic TCD50. Results: Fractionation substantially increased the dose required for tumor control in 4 of the 5 tumors investigated. For these 4 tumors, the rank-order correlation coefficient between the single dose hypoxic versus fractionated dose TCD50s under hypoxic or aerobic conditions was 1.0. For all 5 tumors examined, a trend for rank correlation was observed between the single dose and the fractionated dose TCD50s performed under normal or clamp hypoxic conditions (r=0.7, p=0.16 in both cases). The linear correlation coefficients were 0.83, p=0.08 and 0.72, p=0.17, respectively. Failure to attain a rank correlation of 1.0 was due to one tumor exhibiting an insignificant fractionation effect. The rank correlation between the TCD50s for fractionated treatments under normal versus the extrapolated TCD50s under clamp hypoxic conditions was 1.00; the linear correlation coefficient was 0.97 (p=0.01). Conclusions: In the tumor models examined, factors controlling the single fraction tumor control dose, also impact the response to fractionated treatments. These results suggest that laboratory estimates of intrinsic radiosensitivity and tumor clonogen number at the onset of treatment, will be of use in predicting radiocurability for fractionated treatments, as has been observed for single dose treatments

[en] Purpose: The dose of radiation that locally controls human tumors treated electively or for gross disease is rarely well defined. These doses can be useful in understanding the dose requirements of novel therapies featuring inhomogeneous dosimetry and in an adjuvant setting. The goal of this study was to compute the dose of radiation that locally controls 50% (TCD₅₀) of tumors in human subjects. Methods and Materials: Logit regression was used with data collected from single institutions or from combinations of local control data accumulated from several institutions treating the same disease. Results: 90 dose response curves were calculated; 62 of macroscopic tumor therapy, 28 of elective therapy with surgery for primary control. The mean and median TCD₅₀ for gross disease were 50.0 and 51.9 Gy, respectively. The mean and median TCD₅₀ for microscopic disease control were 39.3 and 37.9 Gy, respectively. At the TCD₅₀, an additional dose of 1 Gy controlled an additional 2.5% (median) additional patients with macroscopic disease and 4.2% (median) additional patients with microscopic disease. For both macro- and microscopic disease, an increase of 1% of dose at the TCD₅₀ increased control rates ∼ 1% (median) or 2-3% (mean). A predominance of dose response curves had shallow slopes accounting for the discrepancy between mean and median values. Conclusion: Doses to control microscopic disease are approximately 12 Gy less than that required to control macroscopic disease, and are about 79% of the dose required to control macroscopic disease. The percentage increase in cures expected for a 1% increase in dose is similar for macroscopic and microscopic disease, with a median value of ∼ 1%/% and a mean of ∼ 2.7%/%

[en] Purpose: Determination of clonogenic cell proliferation of three highly malignant squamous cell carcinomas (SCC) and two glioblastoma cell lines during a 20-day course of fractionated irradiation under in vitro conditions. Methods and Materials: Tumor cells in exponential growth phase were plated in 24-well plastic flasks and irradiated 24 h after plating with 250 kV x-rays at room temperature. Six fractions with single doses between 0.6 and 9 Gy were administered in 1.67, 5, 10, 15, and 20 days. Colony growth was monitored for at least 60 days after completion of irradiation. Wells with confluent colonies were considered as 'recurrences' and wells without colonies as 'controlled'. The dose required to control 50% of irradiated wells (WCD₅₀) was estimated by a logistic regression for the different overall treatment times. The effective doubling time of clonogenic cells (T_eff) was determined by a direct fit using the maximum likelihood method. Results: The increase of WCD₅₀ within 18.3 days was highly significant for all tumor cell lines accounting for 7.9 and 12.0 Gy in the two glioblastoma cell lines and for 12.7, 14.0, and 21.7 Gy in the three SCC cell lines. The corresponding T_effs were 4.4 and 2.0 days for glioblastoma cell lines and 2.4, 4.2, and 1.8 days for SCC cell lines. Population doubling times (PDT) of untreated tumor cells ranged from 1.0 to 1.9 days, showing no correlation with T_effs. T_eff was significantly longer than PDT in three of five tumor cell lines. No significant differences were observed comparing glioblastomas and SCC. Increase of WCD₅₀ with time did not correlate with T_eff but with T_eff* InSF2 (surviving fraction at 2 Gy). Conclusion: The intrinsic ability of SCC and glioblastoma cells to repopulate during fractionated irradiation could be demonstrated. Repopulation induced dose loss per day depends on T_eff and intrinsic radiation sensitivity. Proliferation during treatment was decelerated compared to pretreatment PDT in the majority of cell lines. Pretreatment cell kinetics did not predict for tumor cell proliferation during treatment

[en] To answer the question whether last clonogenic cell should be eradicated for the tumor to be controlled, radiation tumor control study was performed using microscopic tumors of variable sizes ranging from 101 to 105 tumor cells. TCD50's estimated from experimental data were 14.8, 27.1, 42.4, 49.9 and 65.5 Gy for 101, 102, 103, 104 and 105 tumor cells, respectively. Theoretical calculations, assuming that all the clonogenic cells should be inactivated, were 15.65, 28.50, 40.97, 53.41 and 65.85 Gy. From this well matched data, it can be concluded that all the clonogenic cells should be eradicated for tumor control, at least in this tumor model

[en] Purpose: To evaluate the antitumor activity of recombinant human tumor necrosis factor-alpha (rHuTNF-α) on a human glioblastoma multiforme (U87) xenograft in nude mice, and to study the effect of combining rHuTNF-α with local radiation on the tumor control probability of this tumor model. Methods and Materials: U87 xenograft was transplanted SC into the right hindleg of NCr/Sed nude mice (7-8 weeks old, male). When tumors reached a volume of about 110 mm³, mice were randomly assigned to treatment: rHuTNF-α alone compared with normal saline control; or local radiation plus rHuTNF-α vs. local radiation plus normal saline. Parameters of growth delay, volume doubling time, percentage of necrosis, and cell loss factor were used to assess the antitumor effects of rHuTNF-α on this tumor. The TCD₅₀ (tumor control dose 50%) was used as an endpoint to determine the effect of combining rHuTNF-α with local radiation. Results: Tumor growth in mice treated with a dose of 150 μg/kg body weight rHuTNF-α, IP injection daily for 7 consecutive days, was delayed about 8 days compared to that in controls. Tumors in the treatment group had a significantly longer volume doubling time, and were smaller in volume and more necrotic than matched tumors in control group. rHuTNF-α also induced a 2.3 times increase of cell loss factor. The administration of the above-mentioned dose of rHuTNF-α starting 24 h after single doses of localized irradiation under hypoxic condition, resulted in a significant reduction in TCD₅₀ from the control value of 60.9 Gy to 50.5 Gy (p < 0.01). Conclusion: rHuTNF-α exhibits an antitumor effect against U87 xenograft in nude mice, as evidenced by an increased delay in tumor growth as well as cell loss factor. Also, there was an augmentation of tumor curability when given in combination with radiotherapy, resulting in a significantly lower TCD₅₀ value in the treatment vs. the control groups

[en] Purpose: To study the impact of the overall treatment time of fractionated irradiation on the tumor control probability (TCP) of a human soft tissue sarcoma xenograft growing in nude mice, as well as to compare the pretreatment potential doubling time (T_pot) of this tumor to the effective doubling time (T_eff) derived from three different schedules of irradiation using the same total number of fractions with different overall treatment times. Methods and Materials: The TCP was assessed using the TCD₅₀ value (the 50% tumor control dose) as an end point. A total of 240 male nude mice, 7-8 weeks old were used in three experimental groups that received the same total number of fractions (30 fractions) with different overall treatment times. In group 1, the animals received three equal fractions/day for 10 consecutive days, in group 2 they received two equal fractions/day for 15 consecutive days, and in group 3 one fraction/day for 30 consecutive days. All irradiations were given under normal blood flow conditions to air breathing animals. The mean tumor diameter at the start of irradiation was 7-8 mm. The mean interfraction intervals were from 8-24 h. The T_pot was measured using Iododeoxyuridine (IudR) labeling and flow cytometry and was compared to T_eff. Results: The TCD₅₀ values of the three different treatment schedules were 58.8 Gy, 63.2 Gy, and 75.6 Gy for groups 1, 2, and 3, respectively. This difference in TCD₅₀ values was significant (p < 0.05) between groups 1 and 2 (30 fractions/10 days and 30 fractions/15 days) vs. group 3 (30 fractions/30 days). The loss in TCP due to the prolongation of the overall treatment time from 10 days to 30 days was found to be 1.35-1.4 Gy/day. The pretreatment T_pot (2.4 days) was longer than the calculated T_eff in groups 2 and 3 (1.35 days). Conclusion: Our data show a significant loss in TCP with prolongation of the overall treatment time. This is most probably due to an accelerated repopulation of tumor clonogens. The pretreatment T_pot of this tumor model does not reflect the actual doubling of the clonogens in a protracted regimen

[en] Purpose: Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of 1.0 or 1.1, since the available evidence has been interpreted as indicating that the magnitude of RBE variation with treatment parameters is small relative to our abilities to determine RBEs. As substantial clinical experience and additional experimental determinations of RBE have accumulated and the number of proton radiation therapy centers is projected to increase, it is appropriate to reassess the rationale for the continued use of a generic RBE and for that RBE to be 1.0-1.1. Methods and Materials: Results of experimental determinations of RBE of in vitro and in vivo systems are examined, and then several of the considerations critical to a decision to move from a generic to tissue-, dose/fraction-, and LET-specific RBE values are assessed. The impact of an error in the value assigned to RBE on normal tissue complication probability (NTCP) is discussed. The incidence of major morbidity in proton-treated patients at Massachusetts General Hospital (MGH) for malignant tumors of the skull base and of the prostate is reviewed. This is followed by an analysis of the magnitude of the experimental effort to exclude an error in RBE of ≥10% using in vivo systems. Results: The published RBE values, using colony formation as the measure of cell survival, from in vitro studies indicate a substantial spread between the diverse cell lines. The average value at mid SOBP (Spread Out Bragg Peak) over all dose levels is ∼1.2, ranging from 0.9 to 2.1. The average RBE value at mid SOBP in vivo is ∼1.1, ranging from 0.7 to 1.6. Overall, both in vitro and in vivo data indicate a statistically significant increase in RBE for lower doses per fraction, which is much smaller for in vivo systems. There is agreement that there is a measurable increase in RBE over the terminal few millimeters of the SOBP, which results in an extension of the bioeffective range of the beam in the range of 1-2 mm. There is no published report to indicate that the RBE of 1.1 is low. However, a substantial proportion of patients treated at ∼2 cobalt Gray equivalent (CGE)/fraction 5 or more years ago were treated by a combination of both proton and photon beams. Were the RBE to be erroneously underestimated by ∼10%, the increase in complication frequency would be quite serious were the complication incidence for the reference treatment ≥3% and the slope of the dose response curves steep, e.g., a γ₅₀ ∼4. To exclude ≥1.2 as the correct RBE for a specific condition or tissue at the 95% confidence limit would require relatively large and multiple assays. Conclusions: At present, there is too much uncertainty in the RBE value for any human tissue to propose RBE values specific for tissue, dose/fraction, proton energy, etc. The experimental in vivo and clinical data indicate that continued employment of a generic RBE value and for that value to be 1.1 is reasonable. However, there is a local 'hot region' over the terminal few millimeters of the SOBP and an extension of the biologically effective range. This needs to be considered in treatment planning, particularly for single field plans or for an end of range in or close to a critical structure. There is a clear need for prospective assessments of normal tissue reactions in proton irradiated patients and determinations of RBE values for several late responding tissues in laboratory animal systems, especially as a function of dose/fraction in the range of 1-4 Gy

[en] Purpose: This study assesses the long-term outcome of patients with retroperitoneal sarcoma treated by preoperative external beam radiotherapy, resection, and intraoperative electron beam radiation (IOERT). Methods and Materials: From 1980 to 1996, 37 patients were treated with curative intent for primary or recurrent retroperitoneal soft tissue sarcoma. All patients underwent external beam radiotherapy with a median dose of 45 Gy. This was followed by laparotomy, resection, and IOERT, if feasible. Twenty patients received 10-20 Gy of IOERT with 9-15 MeV electrons. These patients were compared to a group of 17 patients receiving preoperative irradiation without IOERT. Results: The 5-yr actuarial overall survival (OS), disease-free survival, local control (LC), and freedom from distant disease of all 37 patients was 50%, 38%, 59%, and 54%, respectively. After preoperative irradiation, 29 patients (78%) underwent gross total resection. For 16 patients undergoing gross total resection and IOERT, OS and LC were 74% and 83%, respectively. In contrast, these results were less satisfactory for 13 patients undergoing gross total resection without IOERT. For these patients, OS and LC were 30% and 61%, respectively. Four patients experienced treatment-related morbidity. Conclusions: In selected patients, IOERT results in excellent local control and disease-free survival with acceptable morbidity