S. Ahrens

Primary metastatic (stage IV) Ewing tumor: Survival analysis of 171 patients from the EICESS studies

BACKGROUND In the multicenter European Intergroup Cooperative Ewings Sarcoma Studies, localized Ewing tumors of bone were treated by combination chemotherapy with surgery and/or radiotherapy. Patients with primary metastases (pm-pts) were treated in high risk protocols. PATIENTS AND METHODS One hundred seventy-seven pm-pts were registered from January 1990 to December 1995, 171 were evaluable for survival analyses. Thirty-six pm-pts received myeloablative megatherapy with stem cell rescue following conventional treatment. Bilateral whole lung irradiation (WLI) was administered in 57 pm-pts with pulmonary involvement. Event-free survival (EFS) rates were estimated by Kaplan-Meier analysis. Prognostic factors were identified by log-rank statistics, Cox procedures and logistic regression. RESULTS Eighty-nine deaths were recorded by 1 February 1997, EFS four years after diagnosis for all 171 pm-pts was 0.27. EFS for isolated lung metastases was 0.34, for bone/bone marrow (BM) metastases, 0.28, and for combined lung plus bone/BM metastases, 0.14 (P < 0.005). WLI improved outcome in case of isolated pulmonary involvement (0.40 vs. 0.19, P < 0.05). In pm-pts with combined pulmonary/skeletal metastases, intensification by megatherapy and/or WLI improved EFS from 0.00 to 0.27 (P = 0.0001). CONCLUSIONS EFS four years after diagnosis in patients with disseminated Ewing tumors is 0.27. Whole lung irradiation and megatherapy improve outcome in subgroups of patients with disseminated Ewing tumors is 0.27. Whole lung irradiation and megatherapy improve outcome in subgroups of patients with disseminated Ewing disease.

Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials.

PURPOSE The impact of different local therapy approaches on local control, event-free survival, and secondary malignancies in the CESS 81, CESS 86, and EICESS 92 trials was investigated. METHODS AND MATERIALS The data of 1058 patients with localized Ewing tumors were analyzed. Wherever feasible, a surgical local therapy approach was used. In patients with a poor histologic response or with intralesional and marginal resections, this was to be followed by radiotherapy (RT). In EICESS 92, preoperative RT was introduced for patients with expected close resection margins. Definitive RT was used in cases in which surgical resection seemed impossible. In CESS 81, vincristine, adriamycin, cyclophosphamide, and actinomycin D was used. In CESS 86, vincristine, adriamycin, ifosfamide, and actinomycin D was introduced for patients with central tumors or primaries >100 cm(3). In CESS 92, etoposide, vincristine, adriamycin, ifosfamide, and actinomycin D was randomized against vincristine, adriamycin, ifosfamide, and actinomycin D in patients with primaries >100 cm(3). RESULTS The rate of local failure was 7.5% after surgery with or without postoperative RT, and was 5.3% after preoperative and 26.3% after definitive RT (p = 0.001). Event-free survival was reduced after definitive RT (p = 0.0001). Irradiated patients represented a negatively selected population with unfavorable tumor sites. Definitive RT showed comparable local control to that of postoperative RT after intralesional resections. Patients with postoperative RT had improved local control after intralesional resections and in tumors with wide resection and poor histologic response compared with patients receiving surgery alone. Patients with marginal resections with or without postoperative radiotherapy showed comparable local control, yet the number of patients with good histologic response was higher in the latter treatment group (72.2% vs. 38.5%). CONCLUSION Patients with resectable tumors after initial chemotherapy had a low local failure rate. With preoperative RT, local control was comparable. RT is indicated to avoid intralesional resections. After intralesional or marginal resections and after a poor histologic response and wide resection, postoperative RT may improve local control.

Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients.

PURPOSE To analyze event-free survival (EFS) and prognostic factors in patients who present with Ewings tumors (ET) of bone and synchronous pulmonary and/or pleural metastases (ppm). PATIENTS AND METHODS Of 1,270 patients (pts) registered at the continental office of the German/European Intergroup Cooperative Ewings Sarcoma Studies (CESS81, CESS86, EICESS92), 114 were diagnosed ET with ppm. Patients underwent neoadjuvant therapy and local treatment of the primary tumor. Whole-lung irradiation 15 to 18 Gy was applied to 75 ppm-pts. EFS and 95% confidence intervals (CIs) were estimated according to the Kaplan-Meier method, and prognostic factors were analyzed by log-rank tests and Cox and logistic regression procedures. RESULTS On November 1, 1997, at a median time under study of 5.9 years, the 5-year EFS was 0.36 (95% CI, 0.26 to 0.46) and the 10-year EFS was 0.30 (95% CI, 0.19 to 0.41). Thirty-seven of 59 (63%) first relapses involved lung and/or pleura, and the lungs were the only site of relapse in 26 of 59 (44%) ppm-pts. Risk factors identified in univariate and multivariate tests were poor response of the primary tumor toward chemotherapy, metastatic lesions in both lungs, and treatment without additional lung irradiation. CONCLUSION Chemotherapy response of the primary tumor is a prognostic factor in patients with ET with ppm. Strategies of treatment intensification warrant further evaluation.

Second malignancies after treatment for Ewing’s sarcoma: a report of the CESS-studies

PURPOSE During recent years, more intensified systemic and local treatment regimens have increased the 5-year survival figures in localized Ewings sarcoma to more than 60%. There is, however, concern about the risk of second malignancies (SM) in long-term survivors. We have analyzed the second malignancies in patients treated in the German Ewings Sarcoma Studies CESS 81 and CESS 86. MATERIALS AND METHODS From January 1981 through June 1991, 674 patients were registered in the two sequential multicentric Ewings sarcoma trials CESS 81 (recruitment period 1981-1985) and CESS 86 (1986-1991). The systemic treatment in both studies consisted of a four-drug-regimen (VACA = vincristine, actinomycin D, cyclophosphamide, and adriamycin; or VAIA = vincristine, actinomycin D, ifosfamide, and adriamycin) and a total number of four courses, each lasting nine weeks, was recommended by the protocol. Local therapy in curative patients was either complete surgery (n = 162), surgery plus postoperative radiotherapy with 36-46Gy (n = 274), or definitive radiotherapy with 46-60Gy (n = 212). The median follow-up at the time of this analysis was 5.1 years, the maximum follow-up 16.5 years. RESULTS The overall survival of all patients including metastatic patients was 55% after 5 years, 48% after 10 years, and 37% after 15 years. Eight out of 674 patients (1.2%) developed a SM. Five of these were acute myelogenic leukemias (n = 4) or MDS (n = 1), and three were sarcomas. The interval between diagnosis of Ewings sarcoma and the diagnosis of the SM was 17-78 months for the four AMLs, 96 months for the MDS and 82-136 months for the three sarcomas. The cumulative risk of an SM was 0.7% after 5 years, 2.9% after 10 years, and 4.7% after 15 years. Out of five patients with AML/MDS, three died of rapid AML-progression, and two are living with disease. Local therapy (surgery vs. surgery plus postoperative irradiation vs. definitive radiotherapy) had no impact on the frequency of AML/MDS, but local therapy did influence the risk of secondary sarcomas. All three patients with secondary sarcomas had received radiotherapy; however, all three sarcomas were salvaged by subsequent treatment and are in clinical remission with a follow-up of 1 month, 4.3 years, and 7.5 years after the diagnosis of the secondary sarcoma. Thus far, SM contributed to less than 1 % (3/328) of all deaths in the CESS-studies. CONCLUSIONS The risk of leukemia after treatment for Ewings sarcoma is probably in the range of 2%. The risk of solid tumors also seems to be low within the first 10 years after treatment and remains in the range of 5 % after 15 years. In the CESS-studies, less than 1% of all deaths within the first 10 years after diagnosis were caused by SM. Effective salvage therapy for secondary sarcomas is feasible.

Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study

BACKGROUND Ewing tumor treatment involves high cumulative doses of alkylating agents and topoisomerase inhibitors, drugs capable of inducing second cancers. We analyzed the second cancer risk in a large cohort of consistently treated patients. PATIENTS AND METHODS Six hundred ninety Ewing tumor patients were treated between 1992 and 1999 with local therapy and vincristine. doxorubicin, ifosfamide and/or cyclophosphamide, and antinomycin D, with or without etoposide as a randomized question. Second cancer incidences were estimated by competing risk analyses; standardized incidence ratios (SIR) in comparison to registry data were compiled. RESULTS After a median observation time of 56 months (32 months for survivors), 6 of 690 patients had developed second cancers: MDS/AML, two, ALL/NHL, two, squamous cell carcinoma, one, liposarcoma, one. SIR were increased 20-30 fold in comparison to the general population. The cumulative second cancer risk five years after diagnosis of the Ewing tumor was 0.0093 for the total group, zero for patients without etoposide, and 0.0118 with etoposide. Additional phase II high-dose therapy increased the risk to 0.0398 after five years. CONCLUSIONS The second cancder risk observed was in the range to be expected in cancer survivors. High-dose therapy, and less markedly, etoposide, may contribute to the overall second cancer risk.

Factors associated with tumor volume and primary metastases in Ewing tumors: Results from the (EI)CESS studies

BACKGROUND Tumor volumes of more than 100 ml and the presence of primary metastases have been identified as determinants of poor prognosis in patients with Ewing tumors. We sought to assess the prevalence of critical tumor size and primary metastases in a large national sample of patients at the time of first diagnosis and to identify factors that are associated with their occurrence. PATIENTS The present report is based on data of 945 German patients who were enrolled into the (EI)CESS therapy studies between 1980 and 1997. It is assumed that registration of German patients with Ewing tumors under the age of 15 years was almost complete since around 1985. Diagnoses of primary tumors were ascertained exclusively by biopsies. Analyses were restricted to patients with Ewing tumors of bone due to the few occurrences in soft tissues. METHODS Tumor volume data as assessed by radiography, computed tomography or nuclear magnetic imaging were available for 821 patients. The diagnosis of primary metastases was based on thoracic computed tomography or on whole body bone scans in 936 patients. Suspicious lesions had to be confirmed by bone marrow biopsies. We explored how year of first diagnosis, age at first diagnosis, sex, histological subtype and site of the primary tumor related to tumor size and presence of metastases by univariate and multivariate statistical techniques. RESULTS Sixty-eight percent of the patients (n = 559) had a volume above 100 ml with smaller tumors being more common in childhood than in late adolescence and early adulthood. Extensive volumes were observed in almost 90% of the tumors located in femur and pelvis while they were less common in other sites (P < 0.001). On average, 26% of all patients presented with clinically apparent primary metastases. The detection rate of metastases was markedly higher in patients diagnosed after 1991 (P < 0.001). Primary metastases were also significantly more common for tumors originating in the pelvis and for peripheral neuroectodermal tumors (PNET; P < 0.01). Tumors greater than 100 ml were positively associated with metastatic disease (P < 0.001). Multivariate analyses, which included simultaneously all univariate predictors in a logistic regression model, indicated that most of the observed associations were essentially unconfounded. The adjusted odds ratios (OR) for the presence of tumor volumes > or = 100 ml were OR = 1.5 per age rise of 10 years, and OR = 5.8 for pelvis and OR = 7.1 for femur as primary tumor site (all P < 0.001). The presence of metastases was significantly associated with the year of diagnosis (OR = 1.9, after 1991 vs. before 1986), pelvis as site of the primary tumor (OR = 1.8), a PNET (OR = 1.5), and tumor size > or = 100 ml (OR = 1.6). CONCLUSIONS In conclusion, we find that the prevalence of established factors for an unfavorable prognosis is disturbingly high among patients diagnosed with Ewing tumors. Recent progress in imaging techniques seems to account for much of the rise in the detection rate of metastases after 1991. We identify age and, in particular pelvic and femoral site as the major determinants of local tumor extension. Occurrence of primary metastases is independently related to tumor size, pelvic site, and PNET.

Radiotherapy in ewing’s sarcoma and PNET of the chest wall: results of the trials cess 81, cess 86 and eicess 92

PURPOSE Treatment results and the pattern of relapse were evaluated in the multimodal treatment of Ewings sarcomas of the chest wall. METHODS AND MATERIALS In a retrospective analysis, 114 patients with non-metastatic Ewings sarcoma of the chest wall were evaluated. They were treated in the CESS 81, CESS 86, or EICESS 92 studies between January 1981 and December 1993. The treatment consisted of polychemotherapy (VACA, VAIA, or EVAIA) and local therapy, either surgery alone (14 patients), radiotherapy alone (28 patients) or a combination of both (71 patients). The median follow-up was 46.6 months (range 5-170). A relapse analysis for all patients with local or combined relapses was performed. RESULTS Overall survival was 60% after 5 years, event-free survival was 50%. Thirty-seven patients had a systemic relapse (32.4%), 11 patients had a local relapse alone (9.6%), and 3 patients had a combined local and systemic relapse (2.6%). The risk to relapse locally after 5 years was 0% after surgery alone, 19% after radiation alone, and 19% after postoperative irradiation. None of the 8 patients with preoperative irradiation have failed locally so far. With the introduction of central radiotherapy planning in CESS 86, local control of irradiated patients improved. Ten of 14 patients with local failure could be evaluated in the relapse analysis: 3 patients had an in-field relapse, 4 patients had a marginal relapse, 2 patients had a relapse outside the radiation fields, and 1 patient failed with pleural dissemination. Six treatment deviations were observed. CONCLUSION Local control was best after surgery alone in a positively selected group of patients. Local control after radiation or combined radiation and surgery was good. With diligent performance of radiotherapy, it will be possible to further improve the results in the radiotherapy group.

HEMITHORAX IRRADIATION FOR EWING TUMORS OF THE CHEST WALL

PURPOSE In the Cooperative Ewings Sarcoma Study 86 and the European Intergroup Cooperative Ewings Sarcoma Study 92, hemithorax irradiation (RT) was performed in patients with Ewing tumors of the chest wall involving the pleura or contaminating the pleural cavity. In a retrospective analysis, the outcomes of these patients were evaluated and compared with those of patients with chest wall tumors who did not receive hemithorax RT. METHODS AND MATERIALS Between 1985 and 1996, 138 patients presented with nonmetastatic Ewing tumors of the chest wall. They were treated in a multimodal treatment regimen that included polychemotherapy and local therapy depending on the tumor characteristics. Hemithorax RT was performed at a dose of 15 Gy for patients <14 years old and 20 Gy for patients >or=14 years old. Forty-two patients received hemithorax RT (Group 1) and 86 patients did not (Group 2). The data were insufficient for the other 10 patients. RESULTS Comparing both groups, the initial pleural effusion, pleural infiltration, and intraoperative contamination of the pleural space were significantly more frequent in Group 1. The event-free survival rate after 7 years was 63% for patients in Group 1 and 46% for patients in Group 2 (not statistically significant). The 7-year local relapse rate (including combined local-systemic relapses) was 12% in Group 1 and 10% in Group 2; the corresponding systemic relapse rates were 22% and 39%. CONCLUSION Patients with chest wall tumors who received hemithorax RT were negatively selected; yet the rate of event-free survival was better for patients who received hemithorax RT than for those who did not (although the difference was not statistically significant). This result was due to a reduction of metastases, mainly lung metastases. Local control was equivalent between the two groups. These favorable results have caused us to continue using hemithorax RT to treat high-risk patients with Ewing tumors of the chest wall.

Effects of Age, Gender and Ear Side on SOAE Parameters in Infancy and Childhood

We investigated 267 infants and children aged 9 days to 16.8 years to study the spontaneous otoacoustic emission (SOAE) data prevalence, number per ear, level and frequency as a function of growth. Dependence on age, gender and ear side was statistically analyzed using the method of generalized estimation equations. Except in the 1st year of life, SOAE prevalence per ear and SOAE number per ear decreased significantly with increasing age. Both SOAE parameters were significantly higher in female than in male subjects, with gender difference of SOAE prevalence per ear being more distinct in the 1st year of life. Although a clear ear side effect on SOAE prevalence per ear could already be seen in ears of female children in this age group, only SOAE number per ear was significantly higher in right ears than in left ears from the 1st year of life on. Except in the first 12 months, SOAE level and SOAE frequency decreased significantly with increasing age. Neither a significant gender difference nor a significant ear side difference could be determined. Our results found in infancy and childhood are discussed within the framework of the current literature.

Prognostic impact of tumor perfusion in MR-imaging studies in Ewing tumors.

Background: Intratumoral hypoxia is associated wit poor prognosis in various solid tumors. Severe and long-lasting hypoxia results in necrosis. The presence of necrosis therefore might also be correlated with unfavorable outcome. This has been demonstrated for head and neck cancer, gliomas and adult soft tissue sarcomas. We have investigated whetehr or not the pattern of contrast enhancement and the presence of visible necrosis on pretreatment MR images has prognostic impact in Ewing tumors. Patients and Methods: From December 1993 through March 1997, 79 patients with Ewing tumors were prospectively analyzed for the presence and amount of necrosis in their tumors. The median age was 12 years (range 4–30 years). The median follow-up at the time of this analyses was 3 years. All patients were treated according to the multicentric EICESS-92 protocol with multiagent chemotherapy (VACA or VAIA or EVAIA) and local therapy (radiotherapy with 50–60 Gy or surgery or surgery with pre- or postoperative irradiation with 45–50 Gy). For the measurement of necrosis, gadolinium contrast-enhanced T1-weighted MR images were used. Necrosis was defined as non-perfused areas in the tumor and the necrotic volume was expressed as percentage of total volume. Results: Out of 79 tumors, 10 (10%) showed no necrosis, 30 (38%) had 1–25% necrosis, 21 (27%) had 26–50% necrosis and the remaining 18 (23%) more than 50% necrosis. There was a correlation between tumor size and necrosis (p = 0.001): the median tumor volume increased with amount of necrosis (47 cm3 in non necrotic tumors, 59 cm3 vs 280 cm3 vs 284 cm3 for tumors with 1–25% vs 26–50% vs > 50% necrosis). Tumor site (central location vs proximal extremities vs distal extremities) had no impact on necrosis (p = 0.71). 23 out of 79 patients had metastases (M1) at the time of diagnosis. The frequency of metastatic spread increased with the amount of necrosis: 1/10 (10%) patients with non-necrotic tumors had metastases vs 7/30 (23%) vs 6/21 (28%) vs 9/18 (50%) for tumors with 1–25% vs 26–50% vs > 50% necrosis. “Unfavorable” metastatic spread (bone or multiple metastases) was only noted in patients with high amount of necrosis (> 25% necrosis) whereas even large tumors did not show unfavorable metastases if they contained no or only small amounts of necrosis. All patients with non-necrotic tumors survived event-free during the observation period. Patients with necrotic tumors had a 3-year event-free survival of 55% (p = 0.06 vs tumors without necrosis). Conclusions: The presence of non-perfused (presumably necrotic) areas on pretreatment contrast-enhanced MR-images is associated with an increased risk of metastases, especially an unfavorable pattern of metastatic spread at diagnosis. This observation may be explained by a more aggressive biological behavior of hypoxic tumor cells. The small group of patients with non-necrotic tumors (13%) had an excellent prognosis suggesting that the absence of necrosis might be helpful in identifying a very favorable prognostic subgroup in Ewing tumors.Hintergrund: Der prätherapeutische Nachweis von Hypoxie und Nekrosen hat bei einigen Tumoren prognostische Bedeutung. Wir haben bei Patienten mit Ewing-Sarkomen auf prätherapeutischen MR-Aufnahmen den Nekroseanteil (= nach Kontrastmittelgabe nicht perfundierte Areale) ermittelt und untersucht, ob dieser Parameter prognostische Bedeutung hat. Patienten und Methodik: Zwischen Dezember 1993 und März 1997 haben wir bei 79 Patienten mit Ewing-Tumoren im Rahmen der zentralen Bestrahlungsplanung in der EICESS-92-Studie prätherapeutische MR-Aufnahmen ohne und mit Kontrastmittelapplikation analysiert. Als Nekrose wurden die Tumoranteile gewertet, die nach Kontrastmittelgabe nich perfundiert waren. Der Nekroseanteil wurde als relativer Anteil des Tumorvolumens geschätzt. Das mediane Alter der 79 Patienten betrug zwölf Jahre (4–30 Jahre). Alle Patienten erhielten eine Kombinationschemotherapie (VACA oder VAIA oder EVAIA) und eine Lokaltherapie, entweder eine alleinige Radiotherapie mit 50–60 Gy oder eine prä- bzw. postoperative Strahlentherapie mit 45–50 Gy oder alleinige Operation. Die mediane Nachbeobachtungszeit betrug 3 Jahre. Ergebnisse: 10/79 (13%) Tumoren hatten keine Nekrose, 30 (38%) waren zu 1–25%, 21 (27%) zu 26–50% und die verbliebenen 18 (23%) in mehr als 50% nekrotisch. Es bestand eine Korrelation zwischen dem Nachweis von Nekrosen und dem Tumorvolumen (p = 0,001): Das mediane Tumorvolumen stieg mit zunehmender Nekrose (47 cm3 in nicht nekrotischen Tumoren, 59 cm3 vs. 280 cm3 vs. 284 cm3 bei Tumoren mit 1–25% vs. 26–50% vs. > 50% Nekrose). Die Tumorlokalisation (zentral vs. proximale Extremitäten vs. distale Extremitäten) hatten keinen Einfluss auf die Nekroserate (p = 0,71). 23/79 Patienten hatten Metastasen (M1) bei Diagnose. Die Metastasierungsfrequenz nahm mit Nekroseanteil zu: 1/10 (10%) Patienten mit nicht nekrotischen Tumoren hatten Metastasen vs. 7/30 (23%) vs. 6/21 (28%) vs. 9/18 (50%) bei Tumoren mit 1–25% vs. 26–50% vs. > 50% Nekrosen. Ein prognostisch ungünstiges Metastasierungsmuster (ossäre Metastasen oder multipler Organbefall) wurde nur bei Tumoren mit einem hohem Nekroseanteil (> 25% Nekrose) beobachtet. Alle Patienten mit nicht nekrotischen Tumoren überlebten ereignisfei nach 3 Jahren, während Patienten mit nekrotischen Tumoren nur ein ereignisfreies 3-Jahres-Überleben von 55% aufwiesen (p = 0,06). Schlussfolgerungen: Der prätherapeutische Nachweis von nicht perfundierten nekrotischen Tumoranteilen ist mit einer ungünstigen Tumorbiologie assoziiert. Umgekehrt haben Patienten mit gut perfundierten Tumoren eine sehr günstige Prognose.