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 Hodgkin's 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 Hodgkin's 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 Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. FUNDING: Deutsche Krebshilfe and the Swiss Federal Government.

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) Hodgkin's 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 Hodgkin's 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 Hodgkin's 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.)

µMLC-LINAC radiosurgery for intracranial meningiomas of complex shape.

BACKGROUND: We present the long-term results of a consecutive series of patients with meningiomas treated by LINAC-radiosurgery using the micro-multi-leaf collimator technique (µMLC). METHODS: Between May 2001 and July 2009, 78 patients (m: f = 024:54; median age, 56.8 years; range, 20.1-81 years) with 87 intracranial meningiomas (78 WHO I, seven WHO II, two WHO III) were treated with µMLC-LINAC radiosurgery at our institution, either as a primary or salvage treatment following one or more microsurgical procedures. Fifty-eight of 87 tumors (66.7%) were located in the skull base. The remaining 29 meningiomas (33.3%) were located in the convexity of the brain. The median tumor volume was 4.8 ml (range, 0.2-18.3 ml). The median tumor surface dose, maximal dose, and therapeutic isodose were 12 Gy, 16 Gy, and 75%, respectively. RESULTS: For retrospective evaluation, we included 70 patients (78 tumors) with a minimum radiological follow-up of 24 months. After a median follow-up of 79.7 months (range, 24.2-109.1 months), 24 patients (34.3%) improved in their clinical status (paresis of N. abducens 18/48, facial paresis 4/8, and hemiparesis 2/9), 41 patients remained stable (58.6%), three patients had treatment-related temporary complaints (4.3%); two patients developed vertigo, and one had a left-sided hemihypesthesia. All complaints recovered completely after steroid medication within 2 weeks. Two patients (2.8%) developed permanent trigeminal neuralgia. Follow-up MR images showed a partial remission in 21 tumors (26.9%) and a stable tumor size in 55 cases (70.5%). Two patients with high-grade meningiomas showed a tumor progression (one WHO II and one WHO III meningioma). At the end of follow-up (July 2010), the actuarial 5- and 9-year progression-free survival after radiosurgery were 98 and 96%, respectively. There was no treatment-related mortality. CONCLUSIONS: LINAC radiosurgery using a micro multi-leaf collimator for complex shaped intracranial meningiomas is effective yielding a high local tumor control, whereas the treatment-related morbidity remains low.

Radiotherapy of splenomegaly : a palliative treatment option for a benign phenomenon in malignant diseases.

PURPOSE: Since the 20(th) century, radiotherapy (RT) has been used for treatment of symptomatic splenomegaly (SM). SM occurs in association with hematologic disorders. The purpose of this analysis was to determine the indication, treatment concepts, and efficiency of RT. MATERIAL AND METHODS: Clinical features, treatment concepts, and outcome data during the past 20 years were analyzed. Endpoints were pain relief, symptomatic and hematological response, and treatment-related side effects. RESULTS: From 1989-2009, a total of 122 patients received 246 RT courses because of symptomatic SM. Overall 31 patients had chronic myelogenous leukemia (CML), 37 had chronic lymphocytic leukemia (CLL), 23 had osteomyelofibrosis (OMF), 17 had polycythemia vera (PV), 5 had acute myelogenous leukemia, 4 had idiopathic thrombocytopenic purpura (ITP), 3 had non-Hodgkin lymphoma (NHL), and 2 had multiple myeloma (MM). Patients were treated with (60)Co gamma rays or 5-15MV photons. The fraction size ranged from 10-200 cGy and the total dose per treatment course from 30-1600 cGy. Significant pain relief was achieved for 74.8% of the RT courses given for splenic pain. At least 50% regression was attained for 77% of the RT courses given for SM. 36 patients died within 2 months due to the terminal nature of their disease. Of the RT courses applied for cytopenia, 73.6% achieved a significant improvement of hematological parameters and reduction of transfusion need. Notable hematologic toxicities were reported < EORTC/RTOG II°. CONCLUSION: The present analysis documents the efficacy of RT. In addition, RT as a palliative treatment option for symptomatic SM should not be forgotten.

Neoadjuvant radiochemotherapy and surgery for advanced rectal cancer : prognostic significance of tumor regression.

PURPOSE: Preoperative radiochemotherapy is widely used in the treatment of locally advanced rectal cancer. The predictive value of response to neoadjuvant treatment remains uncertain. We retrospectively evaluated the impact of downstaging and tumor regression as prognostic factors and its influence on the ability to perform sphincter-sparing surgery. PATIENTS AND METHODS: A total of 72 consecutive patients with advanced rectal cancer were included in this retrospective analysis. All patients were treated with preoperative 5-fluorouracil-based chemotherapy and pelvic radiation with a total dose of 50.4 Gy followed by surgery 6 weeks later. RESULTS: A sphincter-preserving procedure could be performed on 42 patients, and in all 72 patients complete resection (R0) was achieved. A pathological complete response (ypT0, ypN0) was achieved in 8 (11%) patients. None of the patients showing a complete pathological response relapsed or died during the follow-up period. At a median follow-up of 28 months, 65 patients were alive, none of these patients had local recurrence and 15 patients had metastatic disease. Patients showing a complete pathological response had a significantly better 2-year disease-free survival compared to patients with ≥10% residual tumor cells (p = 0.024). Patients < 65 years showed a significantly better response rate, compared with those > 65 years of age (p = 0.036). Acute toxicity was moderate. CONCLUSION: Preoperative radiochemotherapy is an effective and safe treatment for patients with locally advanced rectal cancer. Pathological parameters after preoperative radiochemotherapy, including tumor regression grading, could be correlated with disease-free survival. The impact of tumor regression grading needs to be further validated in prospective clinical trials.

Combined-modality treatment in advanced oral squamous cell carcinoma: Primary surgery followed by adjuvant concomitant radiochemotherapy.

BACKGROUND: The efficacy of adjuvant radiochemotherapy (RCT) in patients with advanced stage head and neck carcinoma has been proven in prospective randomized trials. However, these trials focused on different head and neck sites. Specific analyses for treatment effects in squamous cell carcinoma of the oral cavity (OSCC) are missing. We evaluated our experiences with adjuvant concomitant RCT in advanced OSCC to compare the results with other treatment schemes using adjuvant RCT. PATIENTS AND METHODS: A total of 183 patients with OSCC of UICC stages II-IVb were reviewed retrospectively. All patients were treated with radical surgery followed by adjuvant, conventional fractionated concomitant RCT using carboplatin. Overall survival was plotted by Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analysis. RESULTS: Univariate analysis showed a significant impact of T, N, and UICC stage, histopathologic grading, surgical margins, extracaspular spread (ECS), and lymphangiosis carcinomatosa on overall survival (Table 3). Patients with stage IVa had a higher 5-year overall survival rate (42.8%) than patients with stage IVb (25.0%) (Figure 1). The differences were significant in multivariate analysis (p = 0.033) (Table 4). CONCLUSION: Adjuvant concomitant RCT is an effective treatment in patients with advanced stage OSCC. However, it remains unclear, which patients should be treated with adjuvant RCT. For patients with stage IVb, adjuvant RCT yields poor results. Prospective randomized trials are needed to confirm which patients should be treated with adjuvant RCT.

Definitive radiochemotherapy of advanced head and neck cancer with carboplatin and paclitaxel : a phase II study.

PURPOSE: To report outcome and toxicity of concurrent radiochemotherapy with carboplatin and paclitaxel in advanced squamous cell carcinomas of the oropharynx and hypopharynx. PATIENTS AND METHODS: Advanced inoperable carcinomas of the oropharynx and hypopharynx were treated with either hyper-fractionated, accelerated radiotherapy (50.0 Gy/2.0 with concomitant boost to 69.2 Gy/1.6) or conventional fractionated radiotherapy (70.2-72 Gy/1.8) concurrent with paclitaxel 40 mg/m2 and carboplatin AUC 1 weekly for 6 weeks. Acute and long-term toxicity was measured according to WHO- and CTC-criteria. RESULTS: A total of 84 patients were included between 2000 and 2008. Median follow-up time of patients alive was 36 months. Conventionally fractionated radiotherapy was given to 16 patients, while 68 patients were treated with concomitant boost. Finally, 88.1% of patients received full dose paclitaxel. Acute mucositis ≥ grade 3 was present in 51.2% of patients, while 6% of patients experienced ≥ grade 3 leucopenia and thrombopenia. A supportive gastric feeding tube was implanted in 89.1% of patients. Overall survival after 2 years was 46.3%, progression-free survival after 2 years was 41.0%. There was no significant survival difference between the different radiotherapy protocols. CONCLUSION: Concomitant carboplatin and paclitaxel is feasible and effective in advanced carcinomas of the head and neck.

Evolution of radiation therapy within the German Hodgkin Study Group trials.

Since its beginning, more than 16,000 patients have been enrolled in the multicentric randomized trials of the German Hodgkin Study Group (GHSG) for adult patients. Within 6 study generations, the treatment of Hodgkin lymphoma has been developed stepwise by using the results of the completed protocols. Now the sixth generation is active. According to the role of radiotherapy, the study group successfully evaluated different dose-effect relationships and could also prove the efficacy of involved-field radiotherapy in early stages in combination with effective chemotherapy. Currently, a radiation dose of 20 Gy to the involved field after a mildly aggressive chemotherapy (2 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine [ABVD]) should be the standard for early-favorable stages according to the GHSG classification. In early-unfavorable or intermediate-risk stages, involved-field radiation therapy with 30 Gy is sufficient; the optimal chemotherapy has to be fixed. For the advanced stages, the question of radiotherapy is still unclear. Preliminary results of the GHSG and others show that additive radiotherapy after intensive chemotherapy might be useful for elective subgroups of patients. The extensive radiotherapy quality assurance program, performed by the GHSG and its radiotherapy reference center, has proven to be successful and necessary to ensure that, with reduced radiation doses and reduced radiation volumes, precise radiotherapy, as defined by the protocol, will be performed by the participating radiotherapy departments.

Stereotactic LINAC radiosurgery for incompletely resected or recurrent atypical and anaplastic meningiomas.

BACKGROUND: The optimal management of subtotally resected or recurrent malignant meningiomas remains controversial. We evaluated the efficacy of linear accelerator (LINAC) radiosurgery for atypical and anaplastic meningiomas after incomplete resection or treatment of recurrences. METHODS: Between August 1990 and December 2003, 16 patients with 28 meningiomas WHO II and III were treated by stereotactic LINAC radiosurgery at our institution. The median radiological follow-up was 60.3 months, respectively (range: 7.2-173.9 months). Fourteen tumors in nine patients were classified as WHO II and 14 tumors in seven patients as WHO III. The median surface dose was 14 Gy (range: 10-15 Gy) with a median tumor volume of 4.8 ml (range: 0.51-51.4 ml). RESULTS: Clinical condition improved in four patients, remained unchanged in nine and deteriorated in one. Tumor shrinkage was seen in eight of 28 meningiomas and a stable disease in 12. Eight of 28 meningiomas showed local tumor progression. The overall tumor control rate (TCR) was 84%, 70%, 70% after 3, 5, 10 years. According to grading the corresponding TCR after 3, 5, 10 years was 91%, 81%, 81% for grade II and 77%, 60%, 60% for grade III meningiomas. Overall progression-free survival (PFS) was 74%, 67%, 58% after 3, 5, 10 years. According to grading the PFS after 3, 5, 10 years was 88%, 75%, 75% for grade II meningiomas and 57%, 57%, 43% for grade III meningiomas. CONCLUSION: Our results show the efficacy and safety of LINAC radiosurgery for incompletely resected or recurrent malignant meningiomas with a relatively high local tumor control and low morbidity.

Long-term outcome and prognostic factors in early-stage nodal low-grade non-hodgkin's lymphomas treated with radiation therapy.

PURPOSE: Retrospective analysis of therapy results in patients with stage I-II and limited stage III nodal low-grade non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: The present retrospective study covers 65 patients treated between 1988 and 2006 at the Department of Radiation Oncology, University of Cologne, Germany. 50 patients were treated with radiotherapy alone (EF [extended field]: n = 35, IF/REG [involved field/regional field]: n = 9, TNI/TLI [total nodal/total lymphatic]: n = 6), 15 patients additionally received chemotherapy. Median age was 58 years. 58 patients presented with centroblastic-centrocytic or follicular lymphomas, seven patients had centrocytic lymphomas. Apart from overall and relapse-free survival, relapse patterns were examined and the impacts of patient characteristics and therapy modalities were analyzed. RESULTS: After a median follow-up of 9.1 years, overall 5-year and 10-year survival was 86% and 55%, relapse-free survival was 55% and 37%, respectively. Relapses occurred in 28 patients during the observation period. Overall survival was favorably influenced by low patient age (p = 0.037), centroblastic-centrocytic/follicular histology (p = 0.006), and early disease stage (p = 0.045). Favorable prognostic factors for relapse-free survival were low patient age (p = 0.035) and centroblastic-centrocytic/follicular histology (p = 0.001). CONCLUSION: Radiotherapy of early-stage low-grade NHL is a curative therapy option, particularly in younger patients and patients with follicular histology. Relapse analysis confirmed the benefits of total nodal or total lymphatic irradiation, although the small number of patients needs to be considered.

Radiotherapy does not influence the severe pulmonary toxicity observed with the administration of gemcitabine and bleomycin in patients with advanced-stage Hodgkin's lymphoma treated with the BAGCOPP regimen: a report by the German Hodgkin's Lymphoma Study Group.

PURPOSE: To evaluate the effect of radiotherapy on the severe pulmonary toxicity observed in the pilot study of BAGCOPP (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine) for advanced-stage Hodgkin's lymphoma. METHODS AND MATERIALS: Patients with Stage III or IV Hodgkin's lymphoma or Stage IIB with risk factors participated in this single-arm, multicenter pilot study. RESULTS: Twenty-seven patients were enrolled on the study before its premature closure as a result of the development of serious pulmonary toxicity in 8 patients. The pulmonary toxicity occurred either during or immediately after the BAGCOPP chemotherapy course. Pulmonary toxicity contributed to one early fatality but resolved in the other 7 patients after cessation of gemcitabine and bleomycin, allowing continuation of therapy. Fifteen patients received consolidative radiotherapy, including 4 who previously had pulmonary toxicity. There were no reported cases of radiation pneumonitis and no exacerbation of pulmonary symptoms in the 4 patients who had had previous pulmonary toxicity. CONCLUSIONS: The severe pulmonary toxicity observed in this study has been attributed to an interaction between gemcitabine and bleomycin. Gemcitabine (when administered without bleomycin) remains of interest in Hodgkin's lymphoma and is being incorporated into a new German Hodgkin's Lymphoma Study Group protocol that also includes consolidative radiotherapy. This study supports the concept of the integration of radiotherapy in gemcitabine-containing regimens in Hodgkin's lymphoma if there is an interval of at least 4 weeks between the two modalities and with a schedule whereby radiotherapy follows the chemotherapy.

Quality control of involved field radiotherapy in patients with early-favorable (HD10) and early-unfavorable (HD11) Hodgkin's lymphoma: an analysis of the German Hodgkin Study Group.

PURPOSE: The German Hodgkin Study Group (GHSG) set up a radiotherapy (RT) reference center within the Department of Radiation Oncology at the University of Cologne to undertake quality assurance of the group's clinical studies. In the HD10 trial (early-favorable stages) and HD11 trial (early-unfavorable stages) all patients received involved field (IF)-RT (30 Gy vs. 20 Gy) within a combined-modality approach. For these patients a central prospective review of all diagnostic imaging was performed by expert radiation oncologists to control disease extension and to define IF treatment volume. METHODS AND MATERIALS: On the basis of simulation films, verification films, and radiotherapy case report form (CRF) an expert panel evaluated retrospectively the adequacy of irradiated IF treatment portals according to the RT prescription, applied radiation doses, treatment time, and technical parameters. RESULTS: Between 1999 and 2006 a total of 825 of 1370 randomized patients of the HD10 trial (60%) and 954 of 1422 patients of the HD11 trial (67%) were evaluated by the panel. Radiotherapy was rated as suboptimal in 47% of all reviewed cases. Although the participating RT centers received a precise RT prescription, most difficulties occurred in the adequate coverage of the IF (40%), followed by technical faults (12%). Deviations from the prescribed single daily dose (1.8-2 Gy), weekly dose, and total reference dose were rare (1%). CONCLUSIONS: As a consequence of these findings, radiation oncologists were trained on the definition of IF-RT at GHSG meetings and at the annual meetings of the German Society for Therapeutic Radiation Oncology. Possible correlations between RT quality and relapse rate will be investigated.

A Contribution to solve the problem of the need for consolidative radiotherapy after intensive chemotherapy in advanced stages of Hodgkin's lymphoma--analysis of a quality control program initiated by the radiotherapy reference center of the German Hodgkin Study Group (GHSG).

PURPOSE: The role of radiotherapy (RT) after intensive chemotherapy in patients with advanced stage Hodgkin's lymphoma (HL) is still unclear. The German Hodgkin Study Group (GHSG) randomized HD12 trial was designed to test whether consolidative RT in the region of initial bulky disease and of residual disease is necessary after effective chemotherapy. A quality control program based on a multidisciplinary panel of radiation oncologists, radiologists, and medical oncologists who reviewed all patients' staging and restaging imaging was initiated. METHODS AND MATERIALS: A total of 1661 patients aged 16 to 65 years with HL in Stage IIB (large mediastinal mass and/or E-lesions) or Stage III to IV were randomized from January 1999 to January 2003 according to a factorial design between: 8 esc.BEACOPP + RT (arm A), 8 esc.BEACOPP non-RT (arm B), 4+4BEACOPP + RT (arm C), 4+4BEACOPP non-RT (arm D). RESULTS: In the fifth interim analysis, 1449 patients were eligible for the arm comparison with regard to RT. After a median observation time of 48 months the FFTF rate was 86% and the OS 92%. The FFTF was 95% in the RT arms A+C and 88% in the non-RT arms B+D: no sequential significant difference. One thousand and eighty four patients were evaluated by the panel. The panel defined initial bulky disease in 800 patients and residual disease in 600 patients. The panel recommended continuation of therapy according to the randomization for 934 of 1084 patients and additive RT independently from the randomization arm for 145 of 1084 patients. CONCLUSIONS: The study showed that RT can be reduced substantially after effective chemotherapy. However, because of the irradiation of 10% of patients in the non-RT arms, equivalent effectiveness of a non-RT strategy cannot be proved. A substantial limitation of consolidative RT according to expert panel recommendations appears to be possible without reducing effectiveness.

Salvage radiotherapy in patients with relapsed and refractory Hodgkin's lymphoma: a retrospective analysis from the German Hodgkin Lymphoma Study Group.

PURPOSE: To evaluate treatment outcome and prognostic factors in patients with refractory or first relapsed Hodgkin's disease (HD) treated with salvage radiotherapy (SRT) alone. PATIENTS AND METHODS: From 4,754 patients registered in the database of the German Hodgkin Study Group from 1988 to 1999, 624 patients were identified with progressive disease (n = 202), or with early (n = 170) or late (n = 252) relapsed HD. At first treatment failure, SRT alone was given to 100 patients. Patient characteristics were: median age, 36 years; progressive disease, 47%; early relapse, 23%; late relapse, 30%; and "B" symptoms, 14%. Eighty-five percent of the patients relapsed after cyclophosphamide, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP/ABVD) -like regimens; 8% after bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimens, 7% after first-line radiotherapy alone. RESULTS: The volume irradiated was mantle field in 43% of patients, inverted-Y in 8%, total nodal irradiation in 12%, and involved-field in 37%. The median SRT dose was 40 Gy (range, 15 to 50 Gy). Seventy-seven patients achieved a complete remission and four patients achieved a partial remission. The 5-year freedom from treatment failure and overall survival (OS) rates were 28% and 51%, respectively. In multivariate analysis, significant prognostic factors for OS were B symptoms (P = .018) and stage at relapse (P = .014). For freedom from second failure (FF2F) Karnofsky performance status (P = .0001) was significant. In patients with limited stage at progression/relapse, duration of first remission was significant (P = .04) for FF2F. CONCLUSION: SRT offers an effective treatment for selected subsets of patients with relapsed or refractory HD.

Impact of target point deviations on control and complication probabilities in stereotactic radiosurgery of AVMs and metastases.

OBJECTIVE: Determination of the impact of inaccuracies in the determination and setup of the target point in stereotactic radiosurgery (SRS) on the expectable complication and control probabilities. METHODS: Two randomized samples of patients with arteriovenous malformation (AVM) (n=20) and with brain metastases (n=20) treated with SRS were formed, and the probability for complete obliteration (COP) or complete remission (CRP), the size of the 10 Gy-volume in the brain tissue (VOI10), and the probability for radiation necrosis (NTCP) were calculated. The dose-effect relations for COP and CRP were fitted to clinical data. Target point deviations were simulated through random vectors and the resulting probabilities and volumes were calculated and compared with the values of the treatment plan. RESULTS: The decrease of the relative value of the control probabilities at 1mm target point deviation was up to 4% for AVMs and up to 10% for metastases. At 2 mm the median decrease was 5% for AVMs and 9% for metastases. The value for the target point deviation, at which COP and CRP decreased about 0.05 in 90% of the cases, was 1.3 mm. The increase of NTCP was maximally 0.0025 per mm target point deviation for AVMs and 0.0035/mm for metastases. The maximal increase of VOI10 was 0.7 cm(3)/mm target point deviation in both patient groups. CONCLUSIONS: The upper limit for tolerable target point deviations is at 1.3mm. If this value cannot be achieved during the system test, a supplementary safety margin should be applied for the definition of the target volume. A better accuracy level is desirable, in order to ensure optimal chances for the success of the treatment. The target point precision is less important for the minimization of the probability of radiation necroses.

Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group.

PURPOSE: To investigate whether radiotherapy can be reduced without loss of efficacy from extended field (EF) to involved field (IF) after four cycles of chemotherapy. PATIENTS AND METHODS: Between 1993 and 1998, patients with newly diagnosed early-stage unfavorable HD were enrolled onto this multicenter study. Patients were randomly assigned to receive cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) + doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for two cycles followed by radiotherapy of 30 Gy EF + 10 Gy to bulky disease (arm A) or 30 Gy IF + 10 Gy to bulky disease (arm B). RESULTS: Of 1,204 patients randomly assigned to treatment, 1,064 patients were informative and eligible for the arm comparison (532 patients in arm A; 532 patients in arm B). The median observation time was 54 months. Five years after random assignment, the overall survival (OSran) for all eligible patients was 91% and freedom from treatment failure (FFTFran) was 83%. Survival rates at 5 years after start of radiotherapy revealed no differences for arms A and B, respectively, in terms of FFTF (85.8% and 84.2%) and OS at 5 years (90.8% and 92.4%). There also were no differences between arms A and B, respectively, in terms of complete remission (98.5% and 97.2%), progressive disease (0.8% and 1.9%), relapse (6.4% and 7.7%), death (8.1% and 6.4%), and secondary neoplasia (4.5% and 2.8%). In contrast, acute side effects including leukopenia, thrombocytopenia, nausea, gastrointestinal toxicity, and pharyngeal toxicity were more frequent in the EF arm. CONCLUSION: Radiotherapy volume size reduction from EF to IF after COPP + ABVD chemotherapy for two cycles produces similar results and less toxicity in patients with early-stage unfavorable HD.

Biophysical analysis of the acute toxicity of radiotherapy in Hodgkin's lymphoma--a comparison between extended field and involved field radiotherapy based on the data of the German Hodgkin Study Group.

PURPOSE: To determine biophysical parameters from the complication probability data during and after radiotherapy of Hodgkin's lymphoma (HL), based on the number of gastrointestinal side effects that were found in the multicenter HD8 trial of the German Hodgkin Lymphoma Study Group. METHODS AND MATERIALS: Between 1993 and 1998, 1204 patients with newly diagnosed, histology-proven HL in clinical Stages I/IIA/IIB with defined risk factors and stage IIIA without risk factors were enrolled into the multicenter HD8 study. Patients were randomized to receive two cycles of COPP (cyclophosphamide, vincristine, procarbazine, prednisone) alternating with two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) followed by radiotherapy (RT) of 30 Gy extended field plus 10 Gy to bulky disease (Arm A) or 30 Gy involved field plus 10 Gy to bulky disease (Arm B). For 910 patients, the rates of acute gastrointestinal side effects during and after RT could be determined. Comparison showed differences between Arms A and B (Grade 1-2: 16.6 vs. 3.9; Grade 3-4: 0.9 vs. 0.2; p < 0.001). From the dose-volume histograms for a "standard patient" (volume intestine 2300 cm3), we determined the normal tissue complication probability (NTCP) (V, D, m, n, TD50), the biophysical parameter TD50, and n (volume dependent) in such a manner that the observed NTCP in Arm A in cases of supradiaphragmatic involvement only and in cases of infradiaphragmatic involvement correlated with the calculated values. RESULTS: Of 1,204 patients randomized, 1,064 patients were informative for the comparison of study arms. The median observation time was 54 months. The overall survival for all eligible patients was 91%, and freedom from treatment failure was 83%. Survival rates at 5 years after start of RT revealed no differences in terms of freedom from treatment failure (85.8% in Arm A, 84.2% in Arm B) and overall survival (90.8% and 92.4%). There were also no differences between the two arms in terms of complete remission, progressive disease, relapse, death, and secondary neoplasias. In contrast, acute side effects, including leukopenia, thrombocytopenia, nausea, gastrointestinal toxicity, and pharyngeal toxicity, were more frequent in the extended field arm. Concerning gastrointestinal toxicity, the different radiation treatment volumes resulted in different NTCPs. On the basis of these findings, values of n = 0.09 and TD50 = 32 Gy were derived. However, this biophysical model is sensitive to variations of the parameters. A deviation of 1% of TD50 results in a deviation of 10% of the NTCP. CONCLUSION: Radiotherapy volume reduction from extended field to involved field after two cycles of COPP/ABVD chemotherapy gives similar results and less toxicity in patients with early-stage, unfavorable HL. Biophysical parameters could be determined from the complication probability data after RT of HL. Because of the exponential dependence, this biophysical model is unstable. It represents a "start model" until further data can be incorporated.

Long-term efficacy, curative potential, and prognostic factors of radiotherapy in primary cutaneous B-cell lymphoma.

PURPOSE: Primary cutaneous B-cell lymphomas (PCBCL) are rare and constitute approximately 5-10% of all cutaneous lymphomas. In the literature, conflicting data exist on the optimal treatment modality regarding the efficacy and the relapse rate after radiotherapy (RT) or polychemotherapy. To evaluate the efficacy of RT, patient data from two centers were analyzed and compared with recent reports in the literature. MATERIALS AND METHODS: Between April 1984 and June 2001, 35 patients with PCBCL, 17 men and 18 women ages 27-86 years, were treated with RT alone (29/35 patients) or postoperative RT (6/35 patients). According to the European Organization for Research and Treatment of Cancer classification for PCBCL, this study group included 21 patients (60%) with primary cutaneous follicle center-cell lymphoma, 7 (20%) with primary cutaneous immunocytoma, 4 (11%) with primary cutaneous large B-cell lymphoma (PCLBCL) of the leg, and 3 (9%) provisional types. RESULTS: A total of 34/35 patients achieved an initial complete response after RT. In one additional patient, RT was interrupted after 16 Gy because of fulminant pneumonia. A total of 11/35 (31%) patients developed cutaneous relapse after a median of 11 months. Three patients developed an in-field response and 8 patients an out-field relapse. After a median follow-up of 52 months, 27/35 patients are alive, whereas 8/35 patients died (three deaths resulting from PCBCL and five unrelated to PCBCL). The 5-year overall survival rate was 75% (95% CI: 55-95%). The 5-year relapse-free survival was 50% (95% CI: 32-68%). Univariate and multivariate analysis revealed disseminated primary lesions in at least two noncontiguous anatomic sites and the histologic subtype PCLBCL as unfavorable prognostic factors. CONCLUSIONS: RT of all visible skin lesions is an effective treatment for localized PCBCL. In patients with cutaneous relapses, RT is an effective treatment option as well.

Initiation of a teleradiotherapeutic network for patients in German lymphoma studies.

PURPOSE: Deviations of radiation treatment portals and dose from prospective treatment plans are unfavorable prognostic factors for lymphoma patients. Therefore, an extensive radiotherapy quality assurance program is used in the ongoing German lymphoma studies. The introduction of teleradiotherapy offered the opportunity to optimize and simplify the workflow of these quality assurance programs. The purpose of this report was to evaluate the feasibility of teleradiotherapy and to describe our experiences with these innovative tools. METHODS AND MATERIALS: During this pilot phase, five radiotherapy centers were equipped with the hardware and software that guarantees a rapid and high-quality transfer of imaging data, as well as real-time teleconferences. The workstation consists of standard PCs with Windows NT as the operating system and the commercial telemedicine software Hipax. RESULTS: As a first step, imaging communication between the radiotherapy reference centers in Cologne and Homburg/Saar was established. Subsequently, three additional radiotherapy departments (Universities of Berlin, Münster, and Munich) with large numbers of lymphoma patients were connected. Other study centers delivered digital imaging on mobile data carriers or via an Integrated Services Digital Network point-to-point connection. Communication units were completed for interactive teleconferences. A facility for central online documentation was installed. Telemedical functions were integrated into the ongoing radiotherapy quality assurance program. Since the introduction of a teleradiotherapeutic workstation in the radiotherapy reference center in Cologne in January 2001, the images of 10% (n = 228 patients) of all reviewed cases of the ongoing Hodgkin's disease 10-12 trials were delivered digitally. The amount of digitally available imaging is continuously increasing. CONCLUSION: The introduction of teleradiotherapy improved the dialog between the radiotherapy reference centers and study centers and thus contributed toward high radiotherapy quality for lymphoma patients in Germany.

Centralized radiation oncologic review of cross-sectional imaging of Hodgkin's disease leads to significant changes in required involved field-results of a quality assurance program of the German Hodgkin Study Group.

PURPOSE: To guarantee the treatment quality of involved-field radiotherapy (IF-RT) of patients in the Hodgkin's disease (HD)10 and HD11 trials of the German Hodgkin Study Group, with 460 participating study centers, a quality assurance program was conducted. It was based on a central prospective radiation oncologic review of all patients' entire diagnostic imaging and clinical findings. An individual RT prescription was provided for every study patient. The purpose of the present investigation was to assess the feasibility of such a procedure and its impact on the final definition of disease extension and patient treatment. METHODS AND MATERIALS: Between 1998 and 2002, 1371 patients were enrolled into the HD10 trial (early-stage disease) and 1570 patients into the HD11 trial (intermediate-stage disease). The HD10 trial tested four cycles of Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD) against two cycles of ABVD followed by 20 Gy of IF-RT vs. 30 Gy of IF-RT (four study arms). The HD11 trial compared four cycles of ABVD with four cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) baseline followed by 20 Gy IF-RT vs. 30 Gy IF-RT in a four-arm design. All study centers were required to score disease involvement at a total of 34 possible anatomic sites on case report forms and send them, together with all diagnostic imaging, to the RT reference center in Cologne, Germany. Images were reviewed there by a panel of expert radiation oncologists and radiologists and compared with the case report form. Differences between the disease involvement documented by the participating center and the reference center were recorded. Subsequently, an individualized treatment proposal was compiled. Complete sets of documentation were submitted to the reference center for 89% of the patients in both HD10 and HD11. RESULTS: A considerable proportion of involved sites were incorrectly recorded on the corresponding case report form by the participating center. For patients with early-stage HD (HD10), there was a correction of disease involvement in 49% (593 of 1214 patients) and for patients with intermediate-stage HD (HD11) in 67% (936 of 1397 patients). Most discrepancies were seen in the lower mediastinum (23%), infraclavicular (17%), upper cervical (16%), supraclavicular (13%), and pulmonary hilar region (13%). This resulted in a change of disease stage in 41 of those 1,529 patients whose documented disease involvement had to be corrected (2.7%). Ninety-three patients had to be treated in a different protocol, because of changes in stage and risk factors. Owing to incorrect lymph node documentation of the participating centers, the RT treatment volume had to be enlarged in 891 (34%) and reduced in 82 (3%) of 2,611 patients. CONCLUSION: A central prospective review of patient data and consecutive prescription of individual RT treatment volume is feasible within large multicenter trials for HD. Such a procedure has a significant impact on the correctness of stage definition, allocation to treatment groups, and extent of the IF treatment volume.