Rolf-Peter Müller

Reduced Treatment Intensity in Patients with Early-Stage Hodgkin's Lymphoma

BACKGROUND Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkins lymphoma with a favorable prognosis remains unclear. We therefore conducted a multicenter, randomized trial comparing four treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels. METHODS We randomly assigned 1370 patients with newly diagnosed early-stage Hodgkins lymphoma with a favorable prognosis to one of four treatment groups: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of radiation therapy (group 1), four cycles of ABVD followed by 20 Gy of radiation therapy (group 2), two cycles of ABVD followed by 30 Gy of radiation therapy (group 3), or two cycles of ABVD followed by 20 Gy of radiation therapy (group 4). The primary end point was freedom from treatment failure; secondary end points included efficacy and toxicity of treatment. RESULTS The two chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P=0.39) or overall survival (P=0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% confidence interval [CI], 90.5 to 94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the two-cycle regimen. When the effects of 20-Gy and 30-Gy doses of radiation therapy were compared, there were also no significant differences in freedom from treatment failure (P=1.00) or overall survival (P=0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received four cycles of ABVD and 30 Gy of radiation therapy (group 1). CONCLUSIONS In patients with early-stage Hodgkins lymphoma and a favorable prognosis, treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy. Long-term effects of these treatments have not yet been fully assessed. (Funded by the Deutsche Krebshilfe and the Swiss Federal Government; ClinicalTrials.gov number, NCT00265018.)

Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial

BACKGROUND The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkins lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. METHODS In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkins lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041. FINDINGS Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy. INTERPRETATION Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkins lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. FUNDING Deutsche Krebshilfe and the Swiss Federal Government.

Intensified Chemotherapy and Dose-Reduced Involved-Field Radiotherapy in Patients With Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD11 Trial

PURPOSE Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkins lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied. PATIENTS AND METHODS Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP(baseline)) + 30 Gy of IFRT; or four cycles of BEACOPP(baseline) + 20 Gy of IFRT. RESULTS With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP(baseline) was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP(baseline) and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, -3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP(baseline), 20 Gy was not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, -4.7%; 95% CI, -10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy. CONCLUSION Moderate dose escalation using BEACOPP(baseline) did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.

Role of postoperative radiotherapy in the management of merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumor of the skin with a high potential of locoregional relapse after surgery alone. This report is an update of our experience in the treatment of MCC. From January 1990 to May 2000, 31 patients with MCC, 13 men and 18 women aged between 34 and 92 years, were treated at the University of Cologne, Germany. Primary tumor sites were in the head and neck region in 13 patients, limbs in 13, and trunk in 5. The tumors were stage I in 26 of 31 patients, stage II in 4 of 31 and stage III in 1 of 31. Treatment included surgery alone in 14 of 31 patients, adjuvant postoperative radiotherapy in 16 of 31 patients, 1 of them had incomplete surgery, and definitive radiotherapy in 1 of 31 patients (stage III). Median overall survival (OS) after first diagnosis was 32 months (95% confidence interval: 0-75 months) with a 3-year OS rate of 47% (95% CI: 25-69%). Six of 31 patients relapsed locally after a median of 4 months, 10 of 31 patients developed regional node metastases, and 7 of 31 patients distant metastases. Nine patients died as a direct result of MCC. Locoregional control and disease-free survival were significantly improved in the group with postoperative radiotherapy (p = 0.023). Uni- and multivariate analysis revealed that head and neck location of the tumor and the lack of postoperative radiotherapy are unfavorable prognostic factors. Postoperative radiotherapy to the primary tumor region and the regional lymphatics is effective in the prevention of locoregional recurrence. Prospective clinical trials should be performed to confirm these observations.

Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone.

PURPOSE To show that radiotherapy (RT) dose to the noninvolved extended field (EF) can be reduced without loss of efficacy in patients with early-stage Hodgkins disease (HD). PATIENTS AND METHODS During 1988 to 1994, pathologically staged patients with stage I or II disease who were without risk factors (large mediastinal mass, extranodal lesions, massive splenic disease, elevated erythrocyte sedimentation rate, or three or more involved areas) were recruited from various centers. All patients received 40 Gy total fractionated dose to the involved field areas but were randomly assigned to receive either 40 Gy (arm A) or 30 Gy (arm B) total fractionated dose for the clinically noninvolved EF. No chemotherapy was given. RT films were prospectively reviewed for protocol violations and recurrences retrospectively related to the applied RT. RESULTS Of 382 recruited patients, 376 were eligible for randomized comparison, 190 in arm A and 186 in arm B. Complete remission was attained in 98% of patients in each arm. With a median follow-up of 86 months, 7-year relapse-free survival (RFS) rates were 78% (arm A) and 83% (arm B) (P =.093). The upper 95% confidence limit for the possible inferiority of arm B in RFS was 4%. Corresponding overall survival rates were 91% (arm A) and 96% (arm B) (P =.16). The most common causes of death (n = 27) were cardiorespiratory disease/pulmonary embolisms (seven), second malignancy (six), and HD (five). Protocol violation was associated with significantly poorer RFS. Nonirradiated nodes were involved in 42 of 52 reviewed relapses, infield areas in 18, marginal areas in 17, and extranodal sites in 16. CONCLUSION EF-RT alone attains good survival rates in favorable early-stage HD. The 30-Gy dose is adequate for clinically noninvolved areas. Protocol violation worsens the subsequent prognosis. Relapse patterns suggest that systemic therapy can reduce the 20% long-term relapse rate.

Randomized study of postoperative radiotherapy and simultaneous temozolomide without adjuvant chemotherapy for glioblastoma.

Purpose:To evaluate the efficacy of simultaneous postoperative temozolomide radiochemotherapy in glioblastoma patients.Patients and Methods:From February 2002 to July 2004, n = 65 patients from 11 German centers with macroscopic complete tumor resection were randomized to receive either postoperative radiotherapy alone (RT, n = 35) or postoperative radiotherapy with simultaneous temozolomide (RT + TMZ, n = 30). Patients were stratified according to age (≤/>50 years) and WHO performance score (0–1 vs. 2). RT consisted of 60 Gy in 30 fractions. In the RT + TMZ arm, oral TMZ was administered daily at a dose of 75 mg/m2 including weekends (40–42 doses). Adjuvant treatment was not given, but in both arms, patients with recurrent tumors and in good condition (WHO 0–2) were scheduled for salvage chemotherapy with TMZ.Results:The trial was stopped early due to the results of EORTC-study 26981-22981 that showed a survival benefit for the combination of concomitant and adjuvant TMZ compared to radiotherapy alone. In total, 62/65 patients were evaluable. Stratification variables were well balanced (≤ 50 years 26% vs. 20%, WHO 0–1 91% vs. 100%). Neither overall survival (median 17 vs. 15 months) nor progression-free survival (median 7 vs. 6 months) differed significantly between the two arms. In the RT (RT + TMZ) arm, 76% (62%) of the progressing patients received salvage chemotherapy with TMZ, 36% (50%) had a second resection. There was a time-constant trend for increased general quality of life (EORTC questionnaire QLQ C30) and brain-specific quality of life (EORTC questionnaire B20) in the combined arm. Lymphopenia G3–4 was more frequent (33 vs. 6%) in the RT + TMZ arm.Conclusion:After early closure of this trial, a benefit for progression-free survival for simultaneous TMZ radiochemotherapy alone could not be demonstrated. In both arms, salvage therapies were frequently used and probably had a major effect on overall survival.Ziel:Bestimmung der Effektivität einer alleinigen simultanen, postoperativen Radiochemotherapie mit Temozolomid bei Patienten mit Glioblastom.Patienten und Methodik:Von Februar 2002 bis Juli 2004 wurden n = 65 Patienten aus 11 Zentren nach makroskopischer Tumorresektion randomisiert und erhielten entweder eine postoperative lokale Strahlenbehandlung (RT, n = 35) oder eine simultane Radiochemotherapie mit Temozolomid (RT + TMZ, n = 30). Die Stratifizierung erfolgte anhand des Alters (≤/>50 Jahre) und des Allgemeinzustands (AZ) nach WHO (0–1 vs. 2). Die Bestrahlung wurde mit 60 Gy in 30 Fraktionen durchgeführt. Im RT + TMZ-Arm wurde TMZ oral in einer täglichen Dosis von 75 mg/m2 an allen Bestrahlungstagen und am Wochenende verabreicht (40–42 Dosen). Eine adjuvante Therapie mit TMZ erfolgte nicht, stattdessen war für die Patienten in gutem AZ (WHO 0–2) im Falle einer Tumorprogression in beiden Armen eine Rezidiv-Chemotherapie mit TMZ vorgesehen.Ergebnisse:Die Studie wurde vorzeitig nach der Veröffentlichung der EORTC-Studie 26981-22981 abgebrochen, die eine Verlängerung der Überlebenszeit durch eine simultane und adjuvante Radiochemotherapie mit TMZ gezeigt hatte. Insgesamt waren 62/65 Patienten auswertbar. Die Arme (RT vs. RT + TMZ) waren bezüglich der Stratifikationsvariablen ausgeglichen (≤ 50 Jahre 26% vs. 20%, WHO 0–1 91% vs. 100%). Weder das Gesamtüberleben (Median 17 vs. 15 Monate) noch das progressionsfreie Überleben (Median 7 vs. 6 Monate) unterschieden sich signifikant. In dem RT-(RT + TMZ-)Arm erhielten 76% (62%) der progredienten Patienten eine Rezidiv-Chemotherapie mit Temodal, 36% (50%) wurden nochmals operiert. Für die allgemeine und hirnfunktionsbezogene Lebensqualität (EORTC-Fragebögen QLQ C30 und BN20) zeigte sich in dem RT + TMZ-Arm ein zeitkonstanter Trend für bessere Werte. Im RT + TMZ-Arm war die Häufigkeit einer Lymphopenie Grad 3–4 erhöht (33% vs. 6%).Schlussfolgerung:Nach dem vorzeitigen Abbruch der Studie konnte ein Vorteil bezüglich des progressionsfreien Überlebens für die alleinige simultane Radiochemotherapie mit Temozolomid nicht gezeigt werden. In beiden Armen wurden Rezidivtherapien häufig eingesetzt, diese hatten wahrscheinlich einen erheblichen Einfluss auf das Gesamtüberleben.

Hodgkin's Lymphoma in Adolescents Treated With Adult Protocols: A Report From the German Hodgkin Study Group

PURPOSE The standard of care for adolescent patients with Hodgkins lymphoma (HL) is undefined, particularly the choice between pediatric and adult protocols. Thus, we compared risk factors and outcome of adolescents and young adults treated within study protocols of the German Hodgkin Study Group (GHSG). PATIENTS AND METHODS Three thousand seven hundred eighty-five patients treated within the GHSG studies HD4 to HD9 were analyzed; 557 patients were adolescents age 15 to 20 years, and 3,228 patients were young adults age 21 to 45 years. Results Large mediastinal mass and involvement of three or more lymph node areas were more frequent in adolescents (P < .001). The incidence of other risk factors did not differ significantly between age groups. With a median observation time of 81 months for freedom from treatment failure (FFTF) and 85 months for overall survival (OS), log-rank test showed no significant differences between age groups regarding FFTF (P = .305) and a superior OS (P = .008) for adolescents. Six-year estimates for FFTF and OS were 80% and 94%, respectively, for adolescents and 80% and 91%, respectively, for young adults. After adjustment for other predictive factors, Cox regression analysis revealed age as a significant predictor for OS (P = .004), with a higher mortality risk for young adults. Secondary malignancies were more common in young adults (P = .037). CONCLUSION Outcome of adolescent and young adult patients treated within GHSG study protocols is comparable. These data suggest that adult treatment protocols exhibit a safe and effective treatment option for adolescent patients with HL. However, longer follow-up, including assessment of late toxicity, is necessary for final conclusions.

The Development of Quality Assurance Programs for Radiotherapy within the German Hodgkin Study Group (GHSG) Introduction, Continuing Work, and Results of the Radiotherapy Reference Panel*

Background and Purpose:The German Hodgkin Study Group (GHSG), including more than 500 participating centers, established a central radiotherapy (RT) reference center to improve quality of treatment, starting with the first study generation in 1978. More than 11,000 patients with Hodgkin’s lymphoma (HL) have been enrolled into these trials. Extensive continuing quality assurance programs (QAPs) during the study generations have been performed. The purpose of the present article is to summarize the experiences and results of the performed and ongoing QAPs.Material and Methods:A panel of expert radiation oncologists (second study generation HD4–6, 1988–1994, and third study generation HD7–9, 1993–1998) retrospectively evaluated the adequacy of treatment fields, applied radiation doses, treatment time, and technical parameters. Furthermore, a detailed analysis of relapses in correlation with the performed RT was conducted. For the fourth study generation (HD10–12, 1998–2002), the RT reference center changed from Munich to Cologne. New RT QAPs were initiated according to the demands of the new trials and former programs were enhanced: (1) central prospective radiation oncologic review of cross-sectional imaging (HD10, HD11) to create the individual radiation treatment plan; (2) retrospective analysis of the adequacy of the performed involved-field (IF) RT (HD10, HD11); (3) the multidisciplinary HD12 panel (radiation oncologists, medical oncologists, diagnostic radiologists); (4) initiation and integration of a teleradiotherapy network into the GHSG trials.Results:A strong achievement of these activities in the era of extended-field RT was to show that major deviations of radiation treatment portals and radiation dose from prospective treatment prescriptions revealed to be unfavorable prognostic factors for patients with early-stage HL (HD4). The central prospective radiation oncological review of all diagnostic imaging (HD10, HD11) showed that corrections of disease involvement in 49% of patients (593/1,214) with early stages (HD10) and in 67% of patients (936/1,397) with intermediate stages (HD11) were necessary. These procedures had a significant impact on the correctness of stage definition, allocation to treatment groups and on the extension of the IF treatment volume. Until now, 1,080 patients in HD10 and HD11 have been evaluated retrospectively with regard to the adequacy of the performed IF-RT. Although the participating institutions got a precise RT prescription, interim results reveal deviations in a significant number of cases. In the HD12 trial (advanced stages), a multidisciplinary panel of radiation oncologists, radiologists and medical oncologists reviewed all the diagnostic imaging from diagnosis throughout the treatment in comparison to the documentation forms. For patients with poor response to chemotherapy, the panel recommended RT independent of the randomization. This procedure ensured that patients with a poor response to chemotherapy received additional RT. 1,080 of 1,594 randomized patients (68%) could be analyzed. After chemotherapy, 599 patients (56%) showed residual disease (> 1.5 cm), and in 145/1,080 patients (13.5%) the panel recommended additional RT independent of the randomization arm. The introduction of electronic image transfer optimized and simplified the workflow of the QAPs. Rapid online consultation and real-time teleconferences regarding disease involvement, patient management and communication of the RT prescription with connected hospitals proved to be extremely helpful.Conclusion:Today, radiation oncologists in the GHSG perform a continuous and efficient QAP to improve treatment quality of study patients. For early favorable and unfavorable HL a central prospective review of all diagnostic imaging is performed by expert radiation oncologists to control the disease extension and to define the IF treatment volume. Retrospective analysis of RT portals by an expert panel detects faults in the applied irradiation. Participants are trained on the definition of IF-RT by workshops on the occasion of annual GHSG meetings and on the annual meetings of the German Society of Therapeutic Radiation Oncology (DEGRO). For the advanced stages a multidisciplinary panel evaluates the treatment response to chemotherapy. Patients with a poor response receive additional RT due to the panel’s recommendation. The introduction of teleradiotherapy into the GHSG trials improves the dialogue between the central RT reference center and study participants and thus contributes to high RT quality for study patients.Hintergrund und Ziel:Die Deutsche Hodgkin Lymphom Studiengruppe (DHSG) mit aktuell ca. 500 teilnehmenden Studienzentren hatte bereits seit ihrer ersten Studiengeneration ein radiotherapeutisches Referenzzentrum eingerichtet, um die Qualität der Radiotherapie (RT) zu verbessern. Mehr als 11 000 Patienten mit Hodgkin-Lymphom (HL) konnten in diese Therapieoptimierungsstudien eingebracht werden. Große, kontinuierlich praktizierte Qualitätssicherungsprogramme (QSP) wurden in den verschiedenen Studiengenerationen durchgeführt. Die vorliegende Arbeit soll die Erfahrungen dieser Bemühungen und die Ergebnisse der durchgeführten und derzeit praktizierten QSP aufzeigen.Material und Methodik:Von einem Expertengremium (zweite Studiengeneration HD4–6, 1988–1994, und dritte Generation HD7–9, 1993–1998) wurde nach erfolgter RT eine retrospektive qualitative Bewertung aller Patienten hinsichtlich angewandter Bestrahlungstechniken, bestrahlter Volumina und des Verhältnisses von Bestrahlungszeit zu verabreichter Strahlendosis vorgenommen. Darüber hinaus erfolgten eine detaillierte Analyse und Zuordnung der eingetretenen Rezidive hinsichtlich der durchgeführten Strahlen- und Chemotherapie. In der vierten Studiengeneration (HD10–12, 1998–2002) wechselte das radiotherapeutische Referenzzentrum von München nach Köln. Hier wurden neue QSP initiiert und frühere den aktuellen Bedürfnissen angepasst: 1. zentrale prospektive Planung der Involved-Field-Radiotherapie (IF-RT) auf der Basis der gesamten Schnittbildgebung (HD10, HD11); 2. retrospektive Analyse der durchgeführten IF-RT (HD10, HD11); 3. das interdisziplinäre HD12 Panel; 4. Initiierung und Integration von Teleradiotherapie in die DHSG-Studien.Ergebnisse:Auswertungen dieser systematischen Analysen konnten für die alleinige Extended-Field-RT nachweisen, dass Abweichungen von den prospektiv erstellten Bestrahlungsplänen einen ungünstigen Prognosefaktor für Patienten mit HL in frühen Stadien darstellen (Abbildung 1). Die zentrale prospektive Planung der IF-RT konnte eine hohe Rate korrekturbedürftiger Dokumentationen der Befallsmuster aufzeigen (Tabelle 1). Bei 49% der Patienten (593/1 214) in frühen Stadien (HD10) und in 67% der Patienten (936/1 397) in intermediären Stadien (HD11) waren Korrekturen der befallenen Regionen notwendig. Diese Korrekturen hatten einen signifikanten Einfluss auf das korrekte Krankheitsstadium, die Zuordnung zur adäquaten Behandlungsgruppe und auf die Ausdehnung des IF-RT-Volumens (Tabelle 2). Bislang konnten 1 080 Patienten aus HD10 und HD11 retrospektiv durch das Referenzpanel im Hinblick auf die Qualität der durchgeführten IF-RT analysiert werden. Trotz der zentralen prospektiven RT-Planung durch das Referenzzentrum und der Vorgabe eines entsprechenden IF-RT-Volumens konnten Abweichungen in einer signifikanten Zahl nachgewiesen werden. In der HD12-Studie beurteilte ein interdisziplinäres Panel, bestehend aus Radioonkologen, Radiologen und internistischen Onkologen, die gesamte Bildgebung. Dieses Panel filterte Patienten mit fortgeschrittenem HL heraus, die unzureichend auf die primäre Polychemotherapie angesprochen hatten, und führte diese Hochrisikopatienten einer additiven RT zu. 1 080 von 1 594 Patienten (68%) konnten beurteilt werden. 599 Patienten (56%) zeigten nach der Chemotherapie einen Resttumor (> 1,5 cm), für 145/1 080 Patienten (13,5%) empfahl das Panel eine additive RT unabhängig vom Randomisationsarm. Die Einführung eines elektronischen Bildtransfers konnte die Arbeitsabläufe dieser QSP weiter optimieren. Teleradiologische Konferenzmöglichkeiten zwischen den behandelnden Zentren vor Ort und dem Referenzzentrum bieten die Option, Ad-hoc-Entscheidungen zu differenzierten Fällen treffen zu können. Relevante Bilddaten des Patienten können vor RT-Beginn dem Referenzzentrum nicht nur zur prospektiven Erstellung eines RT-Plans, sondern auch zur Überprüfung der Bestrahlungsvolumina zur Verfügung gestellt werden. Korrekturen der Bestrahlungsfelder können so noch vor Durchführung der Behandlung berücksichtigt werden.Schlussfolgerung:Radioonkologen in der DHSG praktizieren heute effiziente QSP. In den frühen und intermediären Stadien des HL erfolgt eine zentrale prospektive Bildbeurteilung des gesamten Stagings zur Festlegung der Befallslokalisationen und zur Vorgabe eines IF-RT-Volumens. Basierend auf den Ergebnissen der prospektiven RT-Planung und der retrospektiven Beurteilung der IF-RT werden die Studienteilnehmer auf den jährlich stattfindenden Studiengruppentreffen sowie auf dem Deutschen Kongress für Radioonkologie (DEGRO) über die korrekte Dokumentation des HL und über die adäquate Durchführung der IF-RT informiert. In den fortgeschrittenen Stadien überprüft ein interdisziplinäres Panel das Therapieansprechen auf die durchgeführte Chemotherapie und führt Patienten mit schlechtem Therapieansprechen einer additiven RT zu. Die Einführung der Teleradiotherapie verbessert den Dialog und den Konsens zwischen Referenzzentrum und den Studienzentren und trägt so zur Verbesserung der Qualität der RT für Patienten mit HL bei.

Esthesioneuroblastoma in childhood and adolescence. Better prognosis with multimodal treatment

Background and Purpose:Only 3% of all malignant intranasal tumors are esthesioneuroblastomas (ENB) and only 20% of these rare neuroectodermal tumors are diagnosed up to 20 years of age. Radiotherapy and surgery are established treatment modalities for these patients, but the role of chemotherapy, especially in a multimodal approach, is not well defined. To investigate the influence of radio- and chemotherapy, the treatment and course of the disease in children and adolescents with ENB were analyzed retrospectively.Patients and Methods:19 unselected patients (nine male and ten female) diagnosed with ENB ≤ 20 years of age were included in this analysis. Median age at diagnosis was 14.0 years (range, 5–20 years). The tumors were Kadish stage B in 4/19 patients and stage C in 15/19 patients. 17 patients underwent surgery, either without further therapy (n = 4), followed by radiotherapy (n = 1) or as part of multimodal regimens (n = 12). Two patients received radio- and chemotherapy without surgery. Complete resection (R0) was achieved in 15 out of 17 patients with surgery including all five patients with preoperative chemotherapy due to unresectable primary at diagnosis.Results:The 5-year overall survival (OS) for the whole group was 73% ± 12% and the 5-year event-free survival (EFS) 55% ± 13%. None of the four patients with stage B experienced tumor progression so far, whereas seven out of 15 patients with stage C did (5-year EFS 47% ± 14%; not significant). Patients with Kadish stage C and multimodal treatment strategies combing surgery, chemo- and radiotherapy had a significantly better outcome than patients with stage C and less than three treatment modalities (65% ± 17% vs. 20% ± 18%; p = 0.02).Conclusion:These data indicate a benefit of multimodal treatment regimens combining surgery, chemo- and radiotherapy for pediatric patients with ENB Kadish stage C. Chemotherapy appears to improve resectability, EFS, and OS. Radiotherapy is an integral part in the management of children and young adolescents with ENB in Kadish stage B and C.Hintergrund und Ziel:Das Ästhesioneuroblastom macht lediglich 3% aller intranasalen Tumoren aus, und nur 20% dieser seltenen neuroektodermalen Tumoren werden bei Patienten ≤ 20 Jahre diagnostiziert. Radiotherapeutische und chirurgische Verfahren sind etablierte Behandlungsmodalitäten bei dieser Tumorentität. Allerdings ist die Rolle der Chemotherapie, insbesondere in multimodalen Therapiekonzepten, nur wenig definiert. Um den Einfluss der Radio- und Chemotherapie in der Behandlung von Kindern und jungen Erwachsenen mit Ästhesioneuroblastom zu untersuchen, wurde diese retrospektive Analyse durchgeführt.Patienten und Methodik:19 Patienten mit Ästhesioneuroblastom ≤ 20 Jahre (neun männlich und zehn weiblich) wurden in die Analyse eingeschlossen. 4/19 Patienten hatten einen Tumor Stadium Kadish B und 15/19 Patienten ein Stadium C. 17 Patienten waren operiert worden, entweder ohne weitere Therapie (n = 4), gefolgt von einer Radiotherapie (n = 1) oder im Rahmen multimodaler Therapieansätze (n = 12; Tabelle 3). Zwei Patienten hatten eine alleinige Radiochemotherapie erhalten. Bei 15/17 Patienten, die operiert worden waren, wurde eine komplette Resektion erzielt. Bei allen fünf Patienten, die eine neoadjuvante Chemotherapie infolge inoperabler Primärtumoren erhalten hatten, konnte eine R0-Resektion erreicht werden.Results:Das 5-Jahres-Gesamtüberleben (OS) aller Patienten betrug 73% ± 12%, das ereignisfreie 5-Jahres-Überleben (EFS) 55% ± 13% (Abbildung 2). Keiner der vier Patienten im Stadium B entwickelte eine Tumorprogression, wohingegen es bei sieben von 15 Patienten im Stadium C zu einer Tumorprogression kam (5-Jahres-EFS 47% ± 14%; nicht signifikant; Abbildung 3). Patienten mit Stadium C und multimodalen Therapieansätzen (Operation, Radio- und Chemotherapie) hatten einen signifikant besseren Verlauf als Patienten im Stadium C mit weniger als drei Therapiemodalitäten (65% ± 17% vs. 20% ± 18%; p = 0,02; Abbildung 4).Schlussfolgerung:Diese Daten zeigen, dass multimodale Therapiestrategien mit Operation, Chemo- und Radiotherapie für pädiatrische Patienten mit Ästhesioneuroblastom im Stadium Kadish C einen Vorteil im Krankheitsverlauf bringen. Der Einsatz der Chemotherapie scheint die Resektabilität, das EFS und das OS zu verbessern. Die Radiotherapie ist ein integraler Bestandteil in der Behandlung von Kindern und jungen Erwachsenen mit Ästhesioneuroblastom im Stadium B und C.

Lymphocyte‐predominant and classical Hodgkin's lymphoma – comparison of outcomes

Abstract:  Introduction: Lymphocyte predominant Hodgkins lymphoma (LPHL) differs in histological and clinical presentation from classical Hodgkins lymphoma (cHL). Treatment of LPHL patients using standard Hodgkins lymphoma (HL) protocols leads to complete remission (CR) in more than 95% of patients. However, differences in terms of relapse rates, survival and freedom from treatment failure (FFTF) between LPHL and cHL patients were suggested by a recent intergroup analysis. To obtain a more comprehensive picture, we reviewed all LPHL‐cases registered in the GHSG database and compared patient characteristics and treatment outcome with cHL patients. Patients and methods: We retrospectively analyzed 8298 HL patients treated within the GHSG trials (HD4–HD12): 394 LPHL patients and 7904 cHL patients. From 394 LPHL patients 63% were in early stage, 16% in intermediate and 21% in advanced stage of disease. Of the 7904 cHL patients analyzed, 22% were in early, 39% in intermediate and 39% in advanced stages. About 9% of LPHL patients had B symptoms compared to 40% in cHL patients. Results: About 91% LPHL vs. 86% cHL patients in early stages, 86% vs. 83% in intermediate and 79% vs. 75% in advanced stages reached CR/CRu. Additional analysis for LPHL IA patients showed 98% CR/CRu after extended field, 100% after involved field (IF) and 98% CR/CRu after combined modality treatment. About 0.3% LPHL patients developed progressive disease (PD) compared to 3.7% cHL patients. The relapse rate of LPHL patients was very similar to cHL (8.1% vs. 7.9%). There were 2.5% secondary malignancies in LPHL and 3.7% in cHL patients. About 4.3% LPHL patients and 8.8% cHL patients died. The FFTF rates for LPHL and cHL patients at a median observation of 41 or 48 months were 92% and 84%, respectively. The OS for LPHL and cHL patients was 96% and 92%, respectively. Conclusion: The cHL patients present more frequently with advanced stages and B symptoms compared to LPHL patients. There was no difference in treatment outcome in terms of CR/CRu, PD and mortality between LPHL and HL. Surprisingly, there were also no differences in patients with relapse.