Gehan Ea

Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study.

A total of 342 previously untreated eligible children were entered into the first Intergroup Ewings Sarcoma Study (IESS) between May 1973 and November 1978. In group I institutions, patients were randomized between treatment 1 (radiotherapy to primary lesion plus cyclophosphamide, vincristine, dactinomycin, and Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH] [VAC plus ADR]) or treatment 2 (same as treatment 1 without ADR), and group II institutions randomized patients between treatment 2 or treatment 3 (same as treatment 2 plus bilateral pulmonary radiotherapy [VAC plus BPR]). The percentages of patients relapse-free and surviving (RFS) at 5 years for treatments 1, 2, and 3 were 60%, 24%, and 44%, respectively. There was strong statistical evidence of a significant advantage in RFS for treatment 1 (VAC plus ADR) versus 2 (VAC alone) (P less than .001) and 3 (P less than .05) and also of treatment 3 versus 2 (P less than .001). Similar significant results were observed with respect to overall survival. Patients with disease at pelvic sites have significantly poorer survival at 5 years than those with disease at nonpelvic sites (34% v 57%; P less than .001). Among pelvic cases, there was no evidence of differing survival by treatment (P = .81), but among nonpelvic cases, there was strong evidence of differing survival by treatment (P less than .001). The overall percentage of patients developing metastatic disease was 44%; the percentages by treatments 1, 2, and 3 were 30%, 72%, and 42%, respectively. The overall incidence of local recurrence was 15%, and there was no evidence that local recurrence rate differed by treatment. Patient characteristics related to prognosis, both with respect to RFS and overall survival experience, were primary site (nonpelvic patients were most favorable) and patient age (younger patients were more favorable).

Multimodal therapy for the management of localized Ewing's sarcoma of pelvic and sacral bones: a report from the second intergroup study.

A total of 59 eligible patients with localized Ewings sarcoma of the pelvic and sacral bones were entered into a multimodal Intergroup Ewings Sarcoma Study (IESS-II) (1978 to 1982) and compared with a historical control series of 68 patients entered into an earlier multimodal Intergroup Ewings Sarcoma Study (IESS-I) (1973 to 1978). High-dose intermittent multiagent chemotherapy (vincristine, cyclophosphamide, Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH], and dactinomycin) was given to all patients for 6 weeks before and for 70 weeks following local therapy. All patients who had a tumor biopsy or incomplete resection performed received a dose of 55 Gy to the tumor bed. With a median follow-up time of 5.5 years, two of 59 patients (3%) had a local recurrence, five patients (8%) had a local recurrence and metastases, and 17 patients (29%) developed metastases only. There was significant statistical evidence of an advantage in relapse-free survival (RFS) and survival (S) for patients on IESS-II versus IESS-I, P = .006 and P = .002, respectively. At 5 years, the comparison between IESS-II versus IESS-I was 55% versus 23% for RFS and 63% versus 35% for S.

Intergroup Ewing's Sarcoma Study Local Control Related to Radiation Dose, Volume, and Site of Primary Lesion in Ewing's Sarcoma

One hundred ninety‐three patients with localized Ewings sarcoma treated at participating institutions of the Intergroup Ewings Sarcoma Study form the basis for this report. All patients received radiation therapy to the primary lesion and were randomized to receive vincristine, actinomycin‐D, and cyclophosphamide (VAC) plus adriamycin (Regimen I); VAC alone (Regimen II); or VAC and bilateral pulmonary irradiation (Regimen III). Local control was achieved in 96% of the patients in Regimen I, and 86% of the patients in both Regimens II and III. The median duration of follow up was 83 weeks and median survival time was 172 weeks. Incremental doses of irradiation did not result in significant changes in the rate of local control of primary lesions. The local control rate was the same (92%) for tumors treated by means of whole‐bone irradiation or with at least 5 cm of free margin around the lesion. The local control rate decreased to 79% for lesions treated with less than a 5‐cm margin. Excellent control was obtained for lesions involving the skull or spine (100%), and distal bones (fibula, 96% and tibia, 91%). Less favorable control rates were noted for pelvic and humeral lesions (84% and 79%, respectively). Bilateral pulmonary irradiation for subclinical disease played a role in lowering the incidence of lung metastases from 38% to 20% for patients treated with VAC. Lung metastases were similarly decreased (10%) when adriamycin was added to VAC chemotherapy. Cancer 46:516–521, 1980.

Local recurrence, rate and sites of metastases, and time to relapse as a function of treatment regimen, size of primary and surgical history in 62 patients presenting with non-metastatic Ewing's sarcoma of the pelvic bones

This report reviews the experience of 62 patients who presented between 1972 and 1978 with non-metastatic Ewings sarcoma of the pelvis and were entered on IESS I. Seventeen patients (27%) developed a local recurrence, 38 patients (61%) demonstrated metastases and 21 (34%) neither. In the dose range 4000 rad to 6000 rad no dose response could be detected for local control of tumor. Forty-six patients (74%) had a biopsy or exploratory surgery only, 5 patients (8%) had an incomplete resection and 11 patients (18%) had a complete resection of their tumor. In the 46 patients having a biopsy only, 13 developed a local recurrence (28%) as compared to 2 of 11 patients undergoing a complete resection (18%). The most common sites for metastases were lung in 19 patients (31%) and bone in 23 patients (37%). No significant difference was noted in the frequency of overall metastases or metastases to any site between those patients receiving one of the three treatment regimens used in IESS I: VAC and Adriamycin (regimen I), VAC alone (regimen II) and VAC plus bilateral pulmonary irradiation (regimen III). At a median follow-up of 135 weeks no significant difference in median survival could be detected in patients with pelvic primaries between regimens I, II and III. The mean diameter of the pelvic primaries was comparable to the nonpelvic, however, one half of the pelvic cases were in the range 10-15 cm. The median time to relapse of the 241 non-pelvic patients on IESS I was 222 weeks as contrasted with the median time to relapse of 92 weeks in the 62 pelvic patients on the same study (p = 0.002). The possible reasons for the poor prognosis of pelvic primary patients are discussed together with treatment policies that might improve the survival of this group of patients.

The role of radiation therapy in the management of non-metastatic Ewing's Sarcoma of bone. Report of the intergroup Ewing's Sarcoma Study

Abstract The role of radiation therapy in local tumor control and decreased incidence of pulmonary metastasis is reported in 271 patients who were entered into the Intergroup Ewings Sarcoma Study with more than one year follow-up and on whom all radiotherapy records were reviewed. The majority of the patients were irradiated to the primary tumor with doses of 4500 to 6500 rad in five to six weeks in combination with systemic administration of three drugs (vincristine, actinomycin-D and cyclophosphamide) or four drugs (vincristine, actinomycin-D, cyclophosphamide and adriamycin). One of the groups of patients was treated with three drugs and bilateral pulmonary irradiation (1500 rad, uncorrected dose, in two weeks). Preliminary analysis shows an overall local primary tumor control of 89 %. Patients with lesions in the pelvis had a local failure rate of 17% (9 of 52) and in the humerus 23% (7 of 31). Factors affecting local recurrences are analyzed in detail. Distant metastases have been noted in 40% of all patients; the highest proportion was noted in the pelvis (49%). There was a significant difference in the appearance of pulmonary metastases in the patients who were treated with four drugs (9.7%) and in the group who received three drugs and pulmonary irradiation (23.5%) when compared with the patients treated with three drugs only (37%). Intensive chemotherapy and radiotherapy significantly improve local tumor control and survival of patients with localized Ewings sarcoma. However, the high incidence of metastasis suggests the need for more effective systemic chemotherapy to further improve treatment results. It is very important to determine the optimal dose of irradiation and minimal volume to be treated in order to achieve optimal survival and primary tumor control with the least sequela.

Analysis of local tumor control in ewing's sarcoma. Preliminary results of a cooperative intergroup study

This report is a preliminary analysis of the local tumor control in 187 patients treated with multi‐agent chemotherapy and local radiation therapy for non‐metastatic Ewings sarcoma. Patients were treated according to three different regimens, all of which included irradiation of the primary tumor and involved bone (5000‐6000 rads in 5‐6 weeks). The first group was treated with a combination of cyclophosphamide, vincristine, adriamycin and actinomycin‐D. The second group received cyclophosphamide, vincristine and actinomycin‐D. The third group was treated with cyclophosphamide, vincristine and actinomycin‐D in addition to bilateral pulmonary irradiation. The present results, after a median follow‐up of 24‐30 months in the various groups combined, indicate that the local control is 87%. Twenty‐two of 25 local failures appeared within 24 months (88% of recurrences). No difference in time of appearance of local recurrence was noted in the three treatment regimens. The highest incidence of local recurrence has been noted in the humerus (22%), the pelvis (19%), the tibia (14%) and the femur (11%). Sixty‐seven of the 187 patients (35.8%) have developed distant metastases, mostly to the lungs and to other skeletal sites. Of the patients with pelvic primaries, 62% have developed distant metastases followed by the humerus (41%), the femur (36%) and the tibia (24%). A detailed analysis of radiation therapy technical factors was done in 110 patients with complete dosimetry data at the time of this report. There is a trend indicating that patients who received doses over 6000 rads (20/20) or with lower doses combined with chemotherapy containing adriamycin (9/9) have a higher local control. However, the difference with the other groups (67/81‐83%) was not statistically significant. Radiation therapy in combination with multiple chemotherapy is an effective treatment method to control Ewings sarcoma locally. The late effects of this intensive combined therapy must be assessed in long term survivals. Future studies in Ewings sarcoma should attempt to elucidate crucial issues such as the optimal volume of bone that should be irradiated, the potential value of limited surgical resection of gross tumor and the determination of optimal multi‐agent regimens which will enhance local tumor control and diminish distant metastases. Because of the rarity of this tumor, the need for cooperative controlled clinical trials is emphasized. Cancer 40:2864‐2873, 1977.

A computer sub-program for calculating the generalized Wilcoxon test

This subroutine calculates the W statistic and a distribution-free two samples test. It is an extension of the Wilcoxon test. This routine is especially suitable for comparing survival distributions. For example, in a clinical trial it may be required to compare two treatments for their ability to prolong life or maintain a patient in a well state. The two treatment groups are designated Group I and Group II. Uncensored times are those from start of study to failure. Censored times are those from start of study to time of withdrawal alive or time of loss to follow-up. n nA complete discussion of the generalized Wilcoxon test is given by Gehan.

A digital simulation of cell kinetics with application to L-1210 cells

Abstract A computer program has been developed to simulate a model of the normal cell cycle. This model postulates that the length of stay in each state, or “compartment”, of the cell cycle is a stochastic variable following a known probability distribution such as the normal, lognormal, or gamma. Other probability distributions could also be used. Normal cell proliferation can be simulated with the number of cells in each compartment shown for each time period. The model also permits the evaluation of different schedules of treatment on the proliferation of cells; each treatment is assumed to have a specified probability of killing a cell in the various states and this probability remains applicable for the period of activity of the drug. Simulation of the proliferation of L-1210 cells in mice has been accomplished with the program (see long write-up) and the mean and variability of time to death obtained corresponds very closely with the experimental results of Skipper, Schabel, and Wilcox (Cancer Chemotherapy Reports, 35: 1964) if gamma distributions are assumed for the length of stay in each state and if the logarithm of the number of cells required to kill an animal is assumed to follow an exponential distribution with a median of 1.5 × 10 9 .