To determine the activity of radiotherapy in patients with inoperable desmoid-type fibromatosis (DF) a multicenter prospective phase II trial was carried out. Patients with inoperable progressive disease of primary, recurrent or incompletely resected lesions received a dose of 56 Gy in 28 fractions. Follow-up MRI studies were carried out every 3 months for 2 years and thereafter every 6 months. The primary end point was local control rate at 3 years, estimated by a nonparametric method for interval-censored survival data. Secondary end points were objective tumor response, acute and late toxic effect. Forty-four patients (27 F/17 M) were enrolled from 2001 to 2008. Median age was 39.5 years. Main tumor sites included trunk 15 (34.1%) and extremities 27 (61.3%). Median follow-up was 4.8 years. The 3-year local control rate was 81.5% (90% one-sided confidence interval 74% to 100%). Best overall response during the first 3 years was complete response (CR) 6 (13.6%), partial response (PR) 16 (36.4%), stable disease 18 (40.9%), progressive disease 3 (6.8%) and nonassessable 1 (2.3%). Five patients developed new lesions. After 3 years, the response further improved in three patients: (CR 2, PR 1). Acute grade 3 side-effects were limited to skin, mucosal membranes and pain. Late toxic effect consisted of mild edema in 10 patients. Moderate dose radiotherapy is an effective treatment of patients with DF. Response after radiation therapy is slow with continuing regression seen even after 3 years.

There are limited data that define the role of chemotherapy in the treatment of high-grade spindle cell sarcomas of bone, other than osteosarcoma or malignant fibrous histiocytoma (MFH-B). This prospective study evaluates the effect of doxorubicin and cisplatin on these tumours. Thirty-seven patients, age 65 years, with spindle cell sarcoma of bone, except osteosarcoma or MFH-B, were included. Chemotherapy consisted of doxorubicin and cisplatin every 3 weeks for six cycles. Resection was performed after three cycles. In 15 patients with metastases, response assessment showed three complete responses (CR), four stable disease (SD), five progression; three were not evaluable. Median time to progression was 30 months (95% Confidence Interval (CI), 8-51 months) for the operable non-metastatic patients; median survival 41 months (95% CI, 16-82 months). Median time to progression in the metastatic group was 10 months (95% CI, 0-18 months) and median survival was 14 months (95% CI, 4-45 months). This study suggests a limited role for doxorubicin and cisplatin in metastatic high-grade spindle cell sarcoma of bone, other than osteosarcoma or MFH-B cases.

BACKGROUND:We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer.METHODS:After undergoing surgery with curative intent, 167 patients were randomly assigned to receive radiotherapy alone (66 Gy over a period of 6 1/2 weeks) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1, 22, and 43 of the radiotherapy regimen.RESULTS:After a median follow-up of 60 months, the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone (P=0.04 by the log-rank test; hazard ratio for disease progression, 0.75; 95 percent confidence interval, 0.56 to 0.99), with 5-year Kaplan-Meier estimates of progression-free survival of 47 percent and 36 percent, respectively. The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group (P=0.02 by the log-rank test; hazard ratio for death, 0.70; 95 percent confidence interval, 0.52 to 0.95), with five-year Kaplan-Meier estimates of overall survival of 53 percent and 40 percent, respectively. The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group (P=0.007). The estimated five-year cumulative incidence of local or regional relapses (considering death from other causes as a competing risk) was 31 percent after radiotherapy and 18 percent after combined therapy. Severe (grade 3 or higher) adverse effects were more frequent after combined therapy (41 percent) than after radiotherapy (21 percent, P=0.001); the types of severe mucosal adverse effects were similar in the two groups, as was the incidence of late adverse effects.CONCLUSIONS:Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications.

The aim of this study was to examine the strategy, feasibility and outcome of neo-adjuvant chemotherapy, with doxorubicin and ifosfamide, in adult patients with 'high-risk' soft-tissue sarcomas. Patients with 'high-risk' soft-tissue sarcomas, defined as tumours > or =8 cm of any grade, or grade II/III tumours <8 cm, or grade II/III locally recurrent tumours, or grade II/III tumours with inadequate surgery performed in the previous 6 weeks and therefore requiring further surgery, were randomised between either surgery alone or three cycles of 3-weekly doxorubicin 50 mg/m(2) intravenous (i.v.) bolus and ifosfamide 5 g/m(2) (24 h infusion) before surgery. The type of surgery had to be planned at randomisation. Tumours were to be amenable to surgery by amputation, compartmental resection, wide or marginal excision. If chemotherapy was given, surgery had to be performed within 21 days after the last chemotherapy. Patients received postoperative radiotherapy in cases of marginal surgery, microscopically incomplete resection and no further possibility for surgery, and in cases of surgery because of local recurrence. 150 patients were entered into the study and 134 were eligible, 67 in each arm. The most frequent side-effects of chemotherapy were alopecia, nausea and vomiting (95%), and leucocytopenia (32%). One patient died of neutropenic fever after the first cycle of chemotherapy. Chemotherapy did not interfere with planned surgery and did not affect postoperative wound healing. Limb-salvage was achieved in 88%, amputation was necessary in 12% (all according to the plan at randomisation). The trial was closed after completion of phase II, since accrual was too slow to justify expanding the study into the scheduled phase III study. At a median follow-up of 7.3 years, the 5 year disease-free survival is estimated at 52% for the no chemotherapy and 56% for the chemotherapy arm (standard error: 7%) (P=0.3548). The 5 year overall survival for both arms is 64 and 65%, respectively (standard error 7%) (P=0.2204). Neo-adjuvant-chemotherapy with doxorubicin and ifosfamide at these doses and with this schedule was feasible and did not compromise subsequent treatment, surgery with or without radiotherapy. Although not powered to draw definitive conclusions on benefit, but with an at least 7 year median follow-up, the results render it less likely that major survival benefits will be achieved with this type of chemotherapy.

Purpose: (1) To determine whether, in post-operative setting, there are differences in disease-free survival (DSF) (primary endpoint), overall survival (OS) and local control (LC) rates (secondary endpoints) between definitive radiotherapy alone (RT) and concurrent radio-chemotherapy (RT-CT) with high dose cisplatin, in locally advanced squamous cell carcinomas (SCC) of the oral cavity, oropharynx, larynx or hypopharynx; (2) To compare acute and late toxicity risks (secondary endpoints) in the two treatment arms. Material and Methods: From 1994 till 2000, 334 patients from 23 institutions were randomly assigned to either RT with one daily session of 2 Gy, up to 66 Gy in 33 fractions (arm 1), or RT-CT, using the same RT schedule combined to 3 courses of cisplatin, 100 mg/sqm, on D1, D22 and D43 (arm 2). The trial was designed to detect a 15% increase in disease free survival (40% to 55% at 3 years) with a 5% significance level, and a power of 80%. Results: At a median follow-up time of 34 months, 3-year DFS estimates were 41%(+/−5%) in arm 1 and 59%(+/−5%) in arm 2 (p: 0.0096), with OS estimates of 49% and 65%, respectively (p: 0.0057). The respective hazard ratios were 0.563 and 0.646, favouring the experimental arm. Likewise LC and time to progression (TTP) were found to be significantly increased, at 3 years, after RT-CT (p: 0.0014 and 0.0016, respectively). In arm 2, grade 3–4 functional mucosal reactions (FMR) were significantly more frequent than during RT (44.5% vs 21.3%; p: 0.0004), whilst there was no difference in objective mucosal reactions (OMR) between the two arms (p: 0.211). As for grades 3 and 4 chemotherapy-related acute toxicity, granulocytopenia and thrombocytopenia were observed in 10.9% and 1.9% of the cases, respectively. Although the present report does not elicit significant differences in late complications between the 2 arms, longer follow-up is needed for an accurate evaluation of late toxicity in normal tissues. Conclusions: The present analysis demonstrates a significant advantage of post-operative RT-CT as compared to RT alone in patients with locally advanced head and neck SCC, who undergo surgery with a curative intent. This difference is reflected on DFS, OS, LC and TTP. Whereas more patients experience severe FMR during RT-CT, the incidence of OMR is not significantly different between the 2 arms. It is too early to estimate the impact of the 2 treatment arms on occurrence of distant metastases and second primary tumors. Longer follow-up is also needed to estimate the late complication rates in normal tissues. OTHER INVESTIGATORS: P. Maingon, F-Dijon; M. Bolla, F-Grenoble; E. Bardet, F-St Herblain; C. Grandi, I-Milan; H. Nguyen, B-Brussels; R. Soumarova, CZ-Brno; C. Glanzmann, CH-Zürich; S. Roth, D-Düsseldorf; B. Jancar, SL-Ljubljana; E. Junor, UK-Glasgow; F. Dhermain, F-Rouen; D. Morgan, UK-Nottingham; A. Daban, F-Poitiers; H. Kaanders, NL-Nijmegen; M. Sen, T-Izmir; F. Cognetti, I-Rome; J-L. Lefèbvre, F-Lille.

Laboratory and field tests were conducted to evaluate the magnitude and uniformity of spray deposits from several fan nozzle types. The laboratory and field average percent spray recoveries were typically in excess of 80% and often exceeded 90%. Ninety-four percent of the field deposit coefficients of variation (CV) were larger than the corresponding laboratory CVs. The down-and-back @ 45 degrees nozzle orientation improved the uniformity of spray deposits in both laboratory and field tests. These comparative CV results confirm similar results from prior studies for other types of fan nozzles. Regression equations were developed to predict 'percent recovery' and 'CV' for both the laboratory and field data. The ratios of the maximum-to-minimum deposits from all treatments were found to be non-linearly related to the CVs of the deposits. A CV of 15% corresponded to a maximum-to-minimum deposit ratio of about 1.7 indicating that a CV of about 15% or less is a desirable goal for any liquid or granular application. Only one third of the original treatments had field CVs less than or equal to 15% and thus, Here considered to be treatments that would be recommended to producers and applicators.

PURPOSE: Approximately 60% of patients with small-cell lung cancer (SCLC) develop brain metastases. Whole-brain radiotherapy (WBRT) gives symptomatic improvement in more than 50% of these patients. Because brain metastases are a sign of systemic progression, and chemotherapy was found to be effective as well, it becomes questionable whether WBRT is the only appropriate therapy in this situation. PATIENTS AND METHODS: In a phase III study, SCLC patients with brain metastases were randomized to receive teniposide with or without WBRT. Teniposide 120 mg/m 2 was given intravenously three times a week, every 3 weeks. WBRT (10 fractions of 3 Gy) had to start within 3 weeks from the start of chemotherapy. Response was measured clinically and by computed tomography of the brain. RESULTS: One hundred twenty eligible patients were randomized. A 57% response rate was seen in the combined-modality arm (95% confidence interval [CI], 43% to 69%), and a 22% response rate was seen in the teniposide-alone arm (95% CI, 12% to 34%) (P < .001). Time to progression in the brain was longer in the combined-modality group (P = .005). Clinical response and response outside the brain were not different. The median survival time was 3.5 months in the combined-modality arm and 3.2 months in the teniposide-alone arm. Overall survival in both groups was not different (P = .087). CONCLUSION: Adding WBRT to teniposide results in a much higher response rate of brain metastases and in a longer time to progression of brain metastases than teniposide alone. Survival was poor in both groups and not significantly different.

Purpose. Doxorubicin (dox) still appears to be one of the most active drugs in the treatment of soft tissue sarcomas. However, treatment duration is limited due to cumulative cardiotoxicity. A number of small studies from single institutions have suggested activity of other analogues. In two studies the EORTC STBSG tested whether epirubicin (epi) is an alternative to standard dose dox in the treatment of chemonaive patients with advanced soft tissue sarcoma. The present report gives the final results of these studies.Patients/Methods. In the first study 210 patients were randomized to receive either dox or epi both at a dose of 75 mg/m(2) given as bolus injection at 3-week intervals. In the second study 334 patients were randomized to dox 75 mg/m(2), epi 150 mg/m(2) or epi 50 mg/m(2) days 1-3, all given as bolus injection at 3-week intervals.Results. In the first study no differences in median survival and duration of response were found. Of 167 evaluable patients the response rate was slightly in favour of dox (23% vs 18%) but at the expense of more toxicity.These data could suggest that increasing the epi dose may lead to a greater antineoplastic effect with acceptable toxicity. In the second study 15% of 314 evaluable patients had an objective tumour response. There were no differences between the three groups with regard to response rate, progression-free and overall survival, but both dose schedules of epi were more myelotoxic than dox.Conclusion. Regardless of schedule and dose, epi is not superior to dox in the treatment of patients with advanced soft tissue sarcomas. In addition, the results illustrate that the data from small studies of single institutions should always be confirmed by large multi-institutional studies before being taken for granted.

Despite advances in the treatment of primary limb osteosarcoma, the outcome of patients with primary metastatic and axial skeletal disease remains poor. The European Osteosarcoma Intergroup have assessed a combination chemotherapy regimen consisting of ifosfamide (IFOS) 3 g/m2/dl-2, doxorubicin (DOX) 25 mg/m2/dl-3 i.v. bolus and cisplatin (CDDP) 100 mg/m2/dl.One hundred nine previously untreated patients with primary osteosarcoma were registered. Eligibility was confirmed in 103. At presentation, 45 eligible patients had metastatic disease, 15 axial skeletal primary tumours and 43 non-metastatic limb tumours.The major toxicities were myelosuppression (90%, grade 3 or 4) and nausea and vomiting (74%, grade 3 or 4). Overall mean relative dose intensity (RDI) was 80% (88% CDDP, 75% IFOS, 81% DOX). Clinical response as measured by reduction in tumour volume occurred in 36% (95% confidence interval (95% CI): 27%-47%) of primary tumours. Response of pulmonary metastases to chemotherapy was seen in 33% (95% CI: 19%-49%). Good histological response (> or = 90% necrosis of the tumour) occurred in 33% (95% CI: 22%-45%) of resected tumours. Five-year survival was 62% in limb-non-metastatic, 41% in axial skeletal and 16% in limb metastatic patients.This regimen is active in osteosarcoma but does not appear to be more active than the two-drug CDDP-DOX regimen currently recommended by EOI.

Background: Despite advances in the treatment of primary limb osteosarcoma, the outcome of patients with primary metastatic and axial skeletal disease remains poor. The European Osteosarcoma Intergroup have assessed a combination chemotherapy regimen consisting of ifosfamide (IFOS) 3 g/m(2)/d1-2, doxorubicin (DOX) 25 mg/m(2)/d1-3 i.v. bolus and cisplatin (CDDP) 100 mg/m(2)/d1. Patients and methods: One hundred nine previously untreated patients with primary osteosarcoma were registered. Eligibility was confirmed in 103. At presentation, 45 eligible patients had metastatic disease, 15 axial skeletal primary tumours and 43 non-metastatic limb tumours. Results: The major toxicities were myelosuppression (90%, grade 3 or 4) and nausea and vomiting (74%, grade 3 or 4). Overall mean relative dose intensity (RDI) was 80% (88% CDDP, 75% IFOS, 81% DOX). Clinical response as measured by reduction in tumour volume occurred in 36% (95% confidence interval (95% CI): 27%-47%) of primary tumours. Response of pulmonary metastases to chemotherapy was seen in 33% (95% CI: 19%-49%). Good histological response (greater than or equal to 90% necrosis of the tumour) occurred in 33% (95% CI: 22%-45%) of resected tumours. Five-year survival was 62% in limb-non-metastatic, 41% in axial skeletal and 16% in limb metastatic patients. Conclusions: This regimen is active in osteosarcoma but does not appear to be more active than the two-drug CDDP-DOX regimen currently recommended by EOI.

The activity and toxicity of single-agent standard-dose doxorubicin were compared with that of two schedules of high-dose epirubicin. A total of 334 chemonaive patients with histologically confirmed advanced soft-tissue sarcomas received (A) doxorubicin 75 mg m(-2) on day 1 (112 patients), (B) epirubicin 150 mg m(-2) on day 1 (111 patients) or (C) epirubicin 50 mg m(-2) day(-1) on days 1, 2 and 3 (111 patients); all given as bolus injection at 3-week intervals. A median of four treatment cycles was given. Median age was 52 years (19-70 years) and performance score 1 (0-2). Of 314 evaluable patients, 45 (14%) had an objective tumour response (eight complete response, 35 partial response). There were no differences among the three groups. Median time to progression for groups A, B and C was 16, 14 and 12 weeks, and median survival 45, 47 and 45 weeks respectively. Neither progression-free (P = 0.93) nor overall survival (P = 0.89) differed among the three groups. After the first cycle of therapy, two patients died of infection and one owing to cardiovascular disease, all on epirubicin. Both dose schedules of epirubicin were more myelotoxic than doxorubicin. Cardiotoxicity (> or = grade 3) occurred in 1%, 0% and 2% respectively. Regardless of the schedule, high-dose epirubicin is not a preferred alternative to standard-dose doxorubicin in the treatment of patients with advanced soft-tissue sarcomas.

BACKGROUND:A previous trial by the European Osteosarcoma Intergroup (EOI) suggested that a short intensive chemotherapy regimen with doxorubicin and cisplatin might produce survival of operable, non-metastatic osteosarcoma similar to that obtained with complex and longer-duration drug regimens based on the widely used T10 multi-drug protocol. We undertook a randomised multicentre trial to compare these two approaches.METHODS:407 patients with operable, non-metastatic osteosarcoma were randomly assigned the two-drug regimen (six cycles [18 weeks] of doxorubicin 25 mg/m2 on days 1-3 and cisplatin 100 mg/m2 on day 1) or a multi-drug regimen (preoperatively vincristine, high-dose methotrexate, and doxorubicin; postoperatively bleomycin, cyclophosphamide, dactinomycin, vincristine, methotrexate, doxorubicin, and cisplatin; this protocol took 44 weeks). Surgery was scheduled for week 9 for the two-drug group and week 7 for the multi-drug group. Analyses of survival and progression-free survival were by intention to treat.FINDINGS:Of 407 randomised patients, 391 were eligible and have been followed up for at least 4 years (median 5-6 years). Toxic effects were qualitatively similar with the two regimens. However, 188 (94%) of 199 patients completed the six cycles of two-drug treatment, whereas only 97 (51%) of 192 completed 18 or more of the 20 cycles of the multi-drug regimen. The proportion showing a good histopathological response (> 90% tumour necrosis) to preoperative chemotherapy was about 29% with both regimens and was strongly predictive of survival. Overall survival was 65% at 3 years and 55% at 5 years in both groups (hazard ratio 0.94 [95% CI 0.69-1.27]). Progression-free survival at 5 years was 44% in both groups (hazard ratio 1.01 [0.77-1.33]).INTERPRETATION:We found no difference in survival between the two-drug and multi-drug regimens in operable, non-metastatic osteosarcoma. The two-drug regimen is shorter in duration and better tolerated, and is therefore the preferred treatment. However, 5-year survival is still unsatisfactory and new approaches to treatment, such as dose intensification, are needed to improve results.

Background and purpose: To evaluate the efficacy of WBRT as a single treatment modality in patients with brain metastases of small cell lung cancer.Patients and methods: The patients had brain metastases of small cell lung cancer without any sign of tumour outside the brain and were treated with 10 x 3.0 Gy WBRT. Response and neurological functions were evaluated after 6, 18 and 36 weeks.Results: Twenty of 22 eligible patients were evaluable for response. In six patients a complete response was seen and in five patients a partial response was seen giving a response rate of 50% (95% CI 28-72%). Response duration was 5.4 months (range 63-260 days) and median survival was 4.7 months (range 14-743 days). In the majority of patients the first site of progression after WBRT was in the central nervous system. Twelve of the patients had stabilization or improvement of the neurological function.Conclusion: WBRT for brain metastases of small cell lung cancer gives a 50% response rate with stabilization or improvement of neurological function. Response duration and survival are short. (C) 1998 Elsevier Science Ireland Ltd.

This study was undertaken to determine if recombinant interferon-gamma (rIFN-γ) given every other day as maintenance therapy could prolong the survival of patients with small cell lung cancer (SCLC) who achieved a complete or nearly-complete response to induction therapy. A secondary endpoint was to assess the toxicity of alternate day doses of this treatment. One hundred and seventy seven patients in complete or nearly-complete response following chemotherapy with or without thoracic radiotherapy were studied. Patients were randomised to receive either rIFN-γ 4 million units (0.2 mg) subcutaneously every other day for 4 months or observation. One hundred and twenty of the 127 registered patients were eligible; 59 patients received IFN and 61 patients without maintenance therapy were followed. Alternate day IFN was reasonably well tolerated by the majority of patients, but in 12% substantial non-haematological toxicity (including flu-like syndrome) occurred. One of 3 patients with pneumonitis died after having received 3.6 mg IFN. The median survival time from the date of randomisation was 8.9 months for the IFN arm and 9.9 months for the observation arm. rIFN-γ at the dose and schedule used in this study failed to prolong response duration and survival in SCLC patients in complete or nearly-complete response. The toxicity seen with every other day doses of IFN was less than that reported with daily dosing. The hypothesis that this agent may increase the deleterious effects of radiation on normal lung tissue was supported by the development of pneumonitis in 3 cases of whom 1 had a fatal outcome. The results do not warrant further studies with rIFN-γ on maintaining response in SCLC.

PURPOSE To evaluate the effectiveness of alternating or sequential schedules of cyclophosphamide, doxorubicin, and etoposide (CDE) chemotherapy and irradiation in patients with previously untreated small-cell lung cancer (SCLC). MATERIALS AND METHODS A total of 335 eligible patients were randomized between five courses of CDE chemotherapy followed by thoracic irradiation 50 Gy in 20 daily fractions (S) and the same total dose of chemotherapy and irradiation split into four courses of five daily fractions delivered on days 14 to 21 of the second and subsequent chemotherapy courses (A). Patients had a median age of 61 years (range, 33 to 75); 224 (66%) were male; the Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0 or 1 in 311; and 254 had weight loss less than 10%. RESULTS The overall median survival duration was 15 months, with 62% (95% confidence interval [CI], 57% to 67%) 1-year, 25% (95% CI, 20% to 30%) 2-year, and 14% (95% CI, 10% to 18%) 3-year survival rates. There was no significant difference between the arms. The median survival time was 14 months in A and 15 months in S. One-year survival was 60% in A (95% CI, 53% to 67%) and 64% in S (95% CI, 57% to 71%); 2-year survival was 26% in A (95% CI, 19% to 33%) and 23% in S (95% CI, 16% to 30%); and 3-year survival was 12% in A (95% CI, 6% to 18%) and 15% in S (95% CI, 9% to 21%). World Health Organization (WHO) grade 3 and 4 neutropenia occurred in 90% of A and 77% of S patients (P < .001) and WHO grade 3 and 4 thrombocytopenia in 33% of A and 20% of S patients (P < .001). Rates of other acute and late toxicities were similar in both arms. Hematologic toxicity compromised treatment dose delivery; less than 50% of A patients received greater than 95% of prescribed chemotherapy and 77% their full radiation course, compared with 60% and 93% for arm S (P < .009). Local relapse was the site of first failure in 60% of all patients and 75% of these suffered an in-field relapse; no difference could be seen between the two arms. CONCLUSION This trial failed to confirm the superiority of an alternating schedule of delivery. For this combination of chemotherapy and irradiation, hematologic toxicity compromised treatment delivery and could have contributed to the overall result. The poor rates of local control are disappointing and require intensification of the radiation therapy strategy.