Rudolf Schwarz

Osteosarcoma Relapse After Combined Modality Therapy: An Analysis of Unselected Patients in the Cooperative Osteosarcoma Study Group (COSS)

PURPOSE To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma. PATIENTS AND METHODS Five hundred seventy-six consecutive patients who had achieved a first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients). RESULTS After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy. CONCLUSION Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.

Evaluation of Five Radiation Schedules and Prognostic Factors for Metastatic Spinal Cord Compression

PURPOSE To study five radiotherapy (RT) schedules and potential prognostic factors for functional outcome in metastatic spinal cord compression (MSCC). PATIENTS AND METHODS One thousand three hundred four patients who were irradiated from January 1992 to December 2003 were included in this retrospective review. The schedules of 1 x 8 Gy in 1 day (n = 261), 5 x 4 Gy in 1 week (n = 279), 10 x 3 Gy in 2 weeks (n = 274), 15 x 2.5 Gy in 3 weeks (n = 233), and 20 x 2 Gy in 4 weeks (n = 257) were compared for motor function, ambulatory status, and in-field recurrences. The following potential prognostic factors were investigated: age, sex, performance status, histology, number of involved vertebra, interval from cancer diagnosis to MSCC, pretreatment ambulatory status, and time of developing motor deficits before RT. A multivariate analysis was performed with the ordered logit model. RESULTS Motor function improved in 26% (1 x 8 Gy), 28% (5 x 4 Gy), 27% (10 x 3 Gy), 31% (15 x 2.5 Gy), and 28% (20 x 2 Gy); and posttreatment ambulatory rates were 69%, 68%, 63%, 66%, and 74% (P = .578), respectively. On multivariate analysis, age, performance status, primary tumor, involved vertebra, interval from cancer diagnosis to MSCC, pretreatment ambulatory status, and time of developing motor deficits were significantly associated with functional outcome, whereas the RT schedule was not. Acute toxicity was mild, and late toxicity was not observed. In-field recurrence rates at 2 years were 24% (1 x 8 Gy), 26% (5 x 4 Gy), 14% (10 x 3 Gy), 9% (15 x 2.5 Gy), and 7% (20 x 2 Gy) (P < .001). Neither the difference between 1 x 8 Gy and 5 x 4 Gy (P = .44) nor between 10 x 3 Gy, 15 x 2.5 Gy, and 20 x 2 Gy (P = .71) was significant. CONCLUSION The five RT schedules provided similar functional outcome. The three more protracted schedules seemed to result in fewer in-field recurrences. To minimize treatment time, the following two schedules are recommended: 1 x 8 Gy for patients with poor predicted survival and 10 x 3 Gy for other patients. Results should be confirmed in a prospective randomized trial.

Osteosarcoma of the Pelvis: Experience of the Cooperative Osteosarcoma Study Group

PURPOSE To define patients and tumor characteristics as well as therapy results, patients with pelvic osteosarcoma who were registered in the Cooperative Osteosarcoma Study Group (COSS) were analyzed. PATIENTS AND METHODS Sixty-seven patients with a high-grade pelvic osteosarcoma were eligible for this analysis. Fifteen patients had primary metastases. All patients received chemotherapy according to COSS protocols. Thirty-eight patients underwent limb-sparing surgery, 12 patients underwent hemipelvectomy, and 17 patients did not undergo definitive surgery. Eleven patients received irradiation to the primary tumor site: four postoperatively and seven as the only form of local therapy. RESULTS Local failure occurred in 47 of all 67 patients (70%) and in 31 of 50 patients (62%) who underwent definitive surgery. Five-year overall survival (OS) and progression-free survival rates were 27% and 19%, respectively. Large tumor size (P =.0137), primary metastases (P =.0001), and no or intralesional surgery (P <.0001) were poor prognostic factors. In 30 patients with no or intralesional surgery, 11 patients with radiotherapy had better OS than 19 patients without radiotherapy (P =.0033). Among the variables, primary metastasis, large tumor, no or intralesional surgery, no radiotherapy, existence of primary metastasis (relative risk [RR] = 3.456; P =.0009), surgical margin (intralesional or no surgical excision; RR = 5.619; P <.0001), and no radiotherapy (RR = 4.196; P =.0059) were independent poor prognostic factors. CONCLUSION An operative approach with wide or marginal margins improves local control and OS. If the surgical margin is intralesional or excision is impossible, additional radiotherapy has a positive influence on prognosis.

Second and Subsequent Recurrences of Osteosarcoma: Presentation, Treatment, and Outcomes of 249 Consecutive Cooperative Osteosarcoma Study Group Patients

PURPOSE To evaluate patient and tumor characteristics, treatment, and outcomes in a large cohort of unselected patients with second and subsequent recurrences of osteosarcoma. PATIENTS AND METHODS Two hundred forty-nine consecutive patients who had originally received combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group protocols and went on to develop a total of 409 second and subsequent osteosarcoma recurrences were analyzed for patient-, tumor-, and treatment-related factors and outcomes. RESULTS Five-year overall and event-free survival rates were 16% and 9% for 249 second, 14% and 0% for 93 third, 13% and 6% for 38 fourth, and 18% and 0% for 14 fifth recurrences, respectively. The proportion of recurrences confined to the lungs decreased and the proportion of those with chest wall involvement increased with increasing numbers of recurrences. The duration of relapse-free intervals and the number of lesions at recurrence correlated with outcomes. While only one of 205 patients with rerecurrence survived past 5 years without surgical remission, 5-year overall and event-free survival rates were 32% and 18% for 119 second, 26% and 0% for 45 third, 28% and 13% for 20 fourth, and 53% and 0% for five fifth recurrences, respectively, in which a renewed surgical remission was achieved. The use of chemotherapy correlated with longer survival in patients without surgical remissions. CONCLUSION To our knowledge, this is the first report of survival estimates derived from large cohorts of unselected patients with second and subsequent osteosarcoma recurrences. It confirms the overwhelming importance of surgical clearance. Prognostic indicators after rerecurrences resemble those known from first recurrence. The exact role of re-treatment with chemotherapy, particularly in the adjuvant situation, remains to be defined.

EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

This manuscript describes the experience from registration until randomisation for a cohort of 2260 patients with osteosarcoma who joined the EURAMOS-1 trial. This includes pre-operative chemotherapy and surgery. It sets out the practical issues in collaboration and in achieving randomisation.

The Role of Radiotherapy in oseosarcoma

A survey of the literature shows that the experience with radiotherapy (RT) in the local treatment of osteosarcoma (OS) is limited. This is due to various reasons: OS is a rare tumor and surgery is the treatment of choice with high local control rate, and uncertainty exists in regard to the efficacy and tolerance of radiotherapy. Publications on this topic were analyzed and will be reviewed. Furthermore, experience from the Cooperative Osteosarkomstudiengruppe (COSS)-Registry, including 100 patients (pts) treated using radiotherapy for OS, was analyzed. The COSS-registry includes a total of 175 pts (5% of all pts) with histologically proven OS irradiated over the period of 1980-2007. 100 pts were eligible for analysis. The median age was 18 (3-66) years. Indication for RT was a primary tumor in 66, a local recurrence in 11, and metastases in 23 pts. 94 pts got external photontherapy; 2 pts, proton therapy; 2 pts, neutron therapy; and 2 pts, intraoperative RT. In addition, a group of 17 pts received bone-targeted radionuclide therapy by samarium-153-EDTMP-therapy alone or in combination with external RT. The median dose for external RT was 55.8 Gy (30-120). All the pts received chemotherapy in accordance with different COSS-protocols. The median follow-up was 1.5 (0.2-23) years. Survival and local control rates at 5 years were calculated, and univariate and multivariate analyses performed. 41 pts are alive, 59 pts died. The overall survival rate after biopsy was 41% at 5 years, while the overall survival rates after RT for the whole group, for treatment of primary tumors, local recurrence, and metastases were 36%, 55%, 15%, and 0% respectively.In 41 cases, local control was achieved, whereas local progression or local recurrence occurred in 59 cases, with a median time to local recurrence of 0.5 (0.1-4) years after RT. 15 pts were nonresponders to radiotherapy. Local control for the whole group was 30%. Local control rates for combined surgery and RT were significantly better than those for RT alone (48% vs. 22%, p=0.002). Local control for treatment of primary tumors, local recurrence, and metastases were 40%, 17%, and 0% respectively. Local control for pts given an addition of samarium-153-EDTMP was poor, though not statistically significant. A dose of over 60 Gy had no significant effect on local control. Prognostic factors for survival were indication for RT, RT plus surgery vs. RT alone and tumor location. Prognostic factors for local control were indication for RT, and RT plus surgery vs. RT alone. For the majority of pts, surgery remains the local treatment of choice. Radiotherapy is an important option as local treatment of unresectable tumors, following intralesional resection, or as palliation of symptomatic metastases. Survival prognosis of such pts, however, is poor. Despite the fact that many of these pts will eventually die, they may benefit in terms of prolonged survival and prolonged local control. The combination of surgery, radiotherapy, and chemotherapy can be curative. The consistent use of full-dose chemotherapy is of importance for the response to radiotherapy. Prognostic factors for survival are indication for RT, RT plus surgery vs. RT alone and tumor location. Prognostic factors for local control are indication for RT, and RT plus surgery vs. RT alone.

Functional Outcomes and Quality of Life After Radical Prostatectomy Only Versus a Combination of Prostatectomy with Radiation and Hormonal Therapy

BACKGROUND While the optimal use and timing of secondary therapy after radical prostatectomy (RP) remain controversial, there are limited data on patient-reported outcomes following multimodal therapy. OBJECTIVE To assess the impact of additional radiation therapy (RT) and/or androgen deprivation therapy (ADT) on urinary continence, potency, and quality of life (QoL) after RP. DESIGN, SETTING, AND PARTICIPANTS Among 13150 men who underwent RP from 1992 to 2013, 905 received RP + RT, 407 RP + ADT and 688 RP + RT + ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES Urinary function, sexual function, and overall QoL were evaluated annually using self-administered validated questionnaires. Propensity score-matched and bootstrap analyses were performed, and the distributions for all functional outcomes were analyzed as a function of time after RP. RESULTS AND LIMITATIONS Patients who received RP + RT had a 4% higher overall incontinence rate 3 yr after surgery, and 1% higher rate for severe incontinence (>3 pads/24h) compared to matched RP-only patients. ADT further increased the overall and severe incontinence rates by 4% and 3%, respectively, compared to matched RP + RT patients. RP + RT was associated with an 18% lower rate of potency compared to RP alone, while RP + RT + ADT was associated with a further 17% reduction compared to RP + RT. Additional RT reduced QoL by 10% and additional ADT by a further 12% compared to RP only and RP + RT, respectively. The timing of RT after RP had no influence on continence, but adjuvant compared to salvage RT was associated with significantly lower potency (37% vs 45%), but higher QoL (60% vs 56%). Limitations of our study include the observational study design and potential for selection bias in the treatments received. CONCLUSIONS Secondary RT and ADT after RP have an additive negative influence on urinary function, potency, and QoL. Patients with high-risk disease should be counseled before RP on the potential net impairment of functional outcomes due to multimodal treatment. PATIENT SUMMARY Men with high-risk disease choosing surgery upfront should be counseled on the potential need for additional radiation and or androgen deprivation, and the potential net impairment of functional outcomes arising from multimodal treatment.

Experiences with a New High-Dose-Rate Brachytherapy (HDR-BT) Boost Technique for T3b Prostate Cancer

Purpose:Experiences with a new high-dose-rate brachytherapy (HDR-BT) boost technique in 41 patients with stage T3b prostate cancer are presented.Patients and Methods:The patients received 18 Gy of HDR-BT (9 Gy on days 1 + 8) plus 50.4 Gy of EBRT. 20 patients (group A) had BT applicators placed into the prostate alone resulting in 18 Gy to prostate and 0 Gy (tip) to 12 Gy (base) to seminal vesicles (SV). The cumulative EQD2 (equivalent dose in 2-Gy fractions, α/β 1.5 Gy) to the SV was 47.5-73.3 Gy. 21 patients (group B) had BT applicators placed into both prostate and SV resulting in 18 Gy to prostate and to > 80% (but not 100%) of the SV (cumulative EQD2 81.5-101.5 Gy). Both groups were compared for acute and late toxicity and for biochemical relapse-free survival (bRFS).Results:The 3-year bRFS was 57% for group A and 79% for group B patients (p = 0.29). A grade 3 acute toxicity (CTC 2.0) was not observed. Grade 2 acute toxicity (proctitis, cystitis, skin toxicity) was comparable in both groups. A grade 3 late toxicity did not occur. Impotence rates were 35% in group A and 24% in group B, respectively (p = 0.73).Conclusion:The new HDR-BT technique (group B) was associated only with minor acute and late toxicity and appears to result in better bRFS than the conventional HDR-BT technique (group A). The results must be confirmed in a prospective trial.Ziel:Erfahrungen mit einer neuen High-Dose-Rate-Brachytherapie-(HDR-BT-)Boost-Technik bei 41 Patienten mit T3b-Prostatakarzinom (Tabelle 1) werden präsentiert.Patienten und Methodik:Die Patienten erhielten 18 Gy HDR-BT (9 Gy an Tag 1 + 8) plus 50,4 Gy perkutan. Bei 20 Patienten (Gruppe A) wurden BT-Applikatoren nur in der Prostata platziert. Die Dosis betrug 18 Gy in der Prostata sowie 0 Gy (Spitze) bis 12 Gy (Basis) in den Samenblasen (SB). Die kumulative EQD2 („equivalent dose in 2-Gy fractions“, α/β 1,5 Gy) betrug in den SB 47,5-73,3 Gy (Abbildung 2). Bei 21 Patienten (Gruppe B) wurden BT-Applikatoren in der Prostata und den SB platziert (Abbildung 1). Die Dosis in Prostata und > 80% (aber nicht 100%) der SB betrug 18 Gy (kumulative EQD2 81,5-101,5 Gy; Abbildung 2). Die Gruppen wurden hinsichtlich Akut- und Spättoxizität sowie des biochemischen rezidivfreien Überlebens (bRFS) verglichen.Ergebnisse:Das bRFS nach 3 Jahren betrug 57% in Gruppe A und 79% in Gruppe (p = 0,29; Abbildung 3). Eine Grad-3-Akuttoxizität (CTC 2.0) wurde in beiden Gruppen nicht beobachtet. Die Grad-2-Akuttoxizität (Proktitis, Zystitis, Hauttoxizität) war in beiden Gruppen vergleichbar (Abbildung 4). Eine Grad-3-Spättoxizität trat bei keinem Patienten auf. Die Impotenzraten betrugen 35% in Gruppe A und 24% in Gruppe B (p = 0,73).Schlussfolgerung:Die neue HDR-BT-Technik (Gruppe B) ist gut verträglich und scheint mit einem besseren bRFS einherzugehen als die konventionelle HDR-BT-Technik (Gruppe A). Die Ergebnisse müssen in einer prospektiven Studie überprüft werden.

Ergebnisse der Strahlentherapie von Wirbelkörperangiomen

Fragestellung: Analyse unserer Therapieergebnisse bei der Behandlung von symptomatischen Wirbelkörperangiomen und Bewertung der Literatur. Patienten und Methode: Die Daten von zehn im Zeitraum von 1974 bis 1997 bestrahlten Patienten mit symptomatischen Wirbelkörperangiomen wurden retrospektiv ausgewertet. Als Kriterium für den Therapieerfolg wurde die Besserung der Schmerz- und der neurologischen Beschwerdesymptomatik gewertet. Ergebnisse: Bei vier von zehn Patienten wurde eine dauerhafte Schmerzfreiheit, bei weiteren vier eine Schmerzlinderung erzielt. Die initial bestehenden neurologischen Symptome bei drei Fällen bildeten sich bei zwei Patienten komplett und bei einem teilweise zurück. Die akuten Nebenwirkungen waren geringfügig. Spätnebenwirkungen traten nicht auf. Eine Dosis-Wirkungs-Beziehung wurde nicht nachgewiesen. In keinem Fall kam es zu einem Rezidiv. Schlußfolgerung: Wir empfehlen eine Bestrahlung von 30 Gy bei symptomatischen Angiomen als primäre Therapie. Bei beginnender Querschnittssymptomatik mit notwendiger operativer Entlastung ist eine Strahlentherapie auch bei postoperativer Symptomfreiheit zur Verhinderung eines Progresses bzw. Rezidivs sinnvoll.Purpose: Assessment of treatment results of symptomatic vertebral hemangiomas and review of the literature (Table 3). Patients and Methods: Ten patients treated between 1974 to 1997 were retrospectively analyzed. Efficacy of treatment was determined according to improvement of pain and/or neurological symptoms (Table 1). Results: Improvement was achieved in 8 of 10 patients. The initially existing neurological symptoms of 3 patients disappeared completely in 2 cases and improved in 1 case. Acute side effects were slight. Late side effects were not seen. A dose-effect relationship could not be assessed. There was no relapse. Conclusion: Radiotherapy with 30 Gy for symptomatic vertebral angioma as primary therapy is indicated. In case of neurological symptoms a radiotherapy after operative therapy is recommendable even if the patient is free of symptoms to prevent progress or relapse.

Ergebnisse der Strahlentherapie bei Meningeomen mit hohem Rezidivrisiko

ZusammenfassungHintergrundRetrospektive Auswertung der Behandlungsergebnisse der Bestrahlung von Meningeomen mit hohem Rezidivrisiko.Patienten und MethodeIm Zeitraum zwischen 1974 und 1995 wurden an zwei Zentren insgesamt 67 Patienten mit Meningeomen bestrahlt. Der Nachbeobachtungszeitraum betrug im Median 61 Monate (Spanne: 0,8 bis 213 Monate). Die Vorstellung zur Strahlentherapie erfolgte entweder beim Tumorrezidiv oder nach Probeexzision, R1- oder R2-Resektion. Das Verhältnis maligne (n=20): benigne (n=47) Histologien betrug 1⩺2,4. Das mcdiane Alter lag bei 55 Jahren (Spannbreite: sieben bis 77 Jahre). Die Radiatio wurde mit ciner Einzeldosis von 1,5 bis 2 Gy pro Fraktion bis zu ciner Gesamtdosis von 36 bis 79,5 Gy durchgeführt. Die Überlebenskurven wurden nach Kaplan-Meier berechnet. Univariate Vergleiche erfolgten mittels Log-rank-Test, multivariate Analysen mittels Cox-Proportional-Hazards-Model. Um die Häufigkeit signifikanter Einflußfaktoren nicht zu überschätzen, wurde eine Bonferroni-Korrektur durchgeführt.ErgebnisseDas krankheitsspezifische Überleben nach fünf und zehn Jahren betrug 82%±5% (Standardfehler) bzw. 70%±9% mit einer lokalen Kontrolle von 78%±5% bzw. 68%±9%. Bezüglich Histologie, Geschlecht. Gesamtdosis und Behandlungszentrum wurden keine signifikanten Unterschiede in den uni- und multivariaten Vergleichen gefunden. Signifikant war sowohl für die lokale Kontrolle als auch für das krankheitsspezifische Überleben das Alter (univariat p=0,02/0,04; multivariat p=0,03/0,04). Die postoperative R-Situation hatte einen signifikanten Einfluß auf das krankheitsspezifische Überleben (p=0,04) Nach Bonferroni-Korrektur sind diese Signifikanzen nicht mehr nachweisbar. Spätnebenwirkungen, insbesondere Hirnnekrosen, wurden in unserem Patientengut nicht beobachtet.SchlußfolgerungenTrotz des negativ selektierten Patientengutes konnten gute Ergebnisse bezüglich lokaler Kontrolle und Überleben erreicht werden. Dies unterstützt den Stellenwert der Strahlenbehandlung beim Meningeom mit hohem LokalrezidivrisikoAbstractAimRetrospective assessment of the efficacy of radiatiotherapy for meningeomas with high risk for local recurrence.Patients and MethodsRecords of 67 patients with meningeomas treated from 1974 to 1995 at 2 centres were analyzed. Follow-up time ranged from 0.8 to 213 months (median: 61 months). Radiation therapy was given either after local failure or after biopsy or subtotal resection. The ratio between malignant (n=20) and benign (n=47) meningeoma was 1∶2.4. Median age of the patients was 55 years (7 to 77 years). Radiation treatment was given at 1.5 to 2 Gy per fraction to 36 to 79.5 Gy. Survival rates were calculated by the Kaplan-Meier method. Statistical comparisons were performed with the log-rank test and the Cox proportional hazards model. The Bonferroni method was used to correct for multiple comparisons.ResultsFive- and 10-year disease-free survival rates were 82%±5% (standard error) and 70%±9%. Local control rates at 5 and 10 years were 78%±5% and 68%±9%. In uni- and multivariate analysis histology, sex, total dose and center showed no significant influence on the results. Patients age was significant for local control (univariate p=0.02; multivariate p=0.03) and disease-free survival (univariate/multivariate p=0.04). The postoperative tumor burden had a significant influence of disease-free survival (multivariate p=0.04). After Bonferroni correction no significant influence was observed. We did not observe late side effects, especially brain necrosis.ConclusionsDespite of the negative selection of our patients we observed high survival- and local control rates after radiation therapy. This underscores the role of radiation therapy in the treatment of meningeomas with high risk of local failure.AIM Retrospective assessment of the efficacy of radiation therapy for meningiomas with high risk for local recurrence. PATIENTS AND METHODS Records of 67 patients with meningiomas treated from 1974 to 1995 at 2 centres were analyzed. Follow-up time ranged from 0.8 to 213 months (median: 61 months). Radiation therapy was given either after local failure or after biopsy or subtotal resection. The ratio between malignant (n = 20) and benign (n = 47) meningioma was 1:2.4. Median age of the patients was 55 years (7 to 77 years). Radiation treatment was given at 1.5 to 2 Gy per fraction to 36 to 79.5 Gy. Survival rates were calculated by the Kaplan-Meier method. Statistical comparisons were performed with the log-rank test and the Cox proportional hazards model. The Bonferroni method was used to correct for multiple comparisons. RESULTS Five- and 10-year disease-free survival rates were 82% +/- 5% (standard error) and 70% +/- 9%. Local control rates at 5 and 10 years were 78% +/- 5% and 68% +/- 9%. In uni- and multivariate analysis histology, sex, total dose and center showed no significant influence on the results. Patients age was significant for local control (univariate p = 0.02; multivariate p = 0.03) and disease-free survival (univariate/multivariate p = 0.04). The postoperative tumor burden had a significant influence of disease-free survival (multivariate p = 0.04). After Bonferroni correction no significant influence was observed. We did not observe late side effects, especially brain necrosis. CONCLUSIONS Despite of the negative selection of our patients we observed high survival- and local control rates after radiation therapy. This underscores the role of radiation therapy in the treatment of meningiomas with high risk of local failure.