Christian Ruebe

Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60)

BACKGROUND Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is used to treat patients with non-Hodgkin lymphoma. Interval decrease from 3 weeks of treatment (CHOP-21) to 2 weeks (CHOP-14), and addition of rituximab to CHOP-21 (R-CHOP-21) has been shown to improve outcome in elderly patients with diffuse large B-cell lymphoma (DLBCL). This randomised trial assessed whether six or eight cycles of R-CHOP-14 can improve outcome of these patients compared with six or eight cycles of CHOP-14. METHODS 1222 elderly patients (aged 61-80 years) were randomly assigned to six or eight cycles of CHOP-14 with or without rituximab. Radiotherapy was planned to sites of initial bulky disease with or without extranodal involvement. The primary endpoint was event-free survival; secondary endpoints were response, progression during treatment, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat. The trial is registered on National Cancer Institute website, number NCT00052936 and as EU-20243. FINDINGS 3-year event-free survival was 47.2% after six cycles of CHOP-14 (95% CI 41.2-53.3), 53.0% (47.0-59.1) after eight cycles of CHOP-14, 66.5% (60.9-72.0) after six cycles of R-CHOP-14, and 63.1% (57.4-68.8) after eight cycles of R-CHOP-14. Compared with six cycles of CHOP-14, the improvement in 3-year event-free survival was 5.8% (-2.8-14.4) for eight cycles of CHOP-14, 19.3% (11.1-27.5) for six cycles of R-CHOP-14, and 15.9% (7.6-24.2) for eight cycles of R-CHOP-14. 3-year overall survival was 67.7% (62.0-73.5) for six cycles of CHOP-14, 66.0% (60.1-71.9) for eight cycles of CHOP-14, 78.1% (73.2-83.0) for six cycles of R-CHOP-14, and 72.5% (67.1-77.9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by -1.7% (-10.0-6.6) after eight cycles of CHOP-14, 10.4% (2.8-18.0) after six cycles of R-CHOP-14, and 4.8% (-3.1-12.7) after eight cycles of R-CHOP-14. In a multivariate analysis that used six cycles of CHOP-14 without rituximab as the reference, and adjusting for known prognostic factors, all three intensified regimens improved 3-year event-free survival (eight cycles of CHOP-14: RR [relative risk] 0.76 [0.60-0.95], p=0.0172; six cycles of R-CHOP-14: RR 0.51 [0.40-0.65], p<0.0001; eight cycles of R-CHOP-14: RR 0.54 [0.43-0.69], p<0.0001). Progression-free survival improved after six cycles of R-CHOP-14 (RR 0.50 [0.38-0.67], p<0.0001), and eight cycles of R-CHOP-14 (RR 0.59 [0.45-0.77], p=0.0001). Overall survival improved only after six cycles of R-CHOP-14 (RR 0.63 [0.46-0.85], p=0.0031). In patients with a partial response after four cycles of chemotherapy, eight cycles were not better than six cycles. INTERPRETATION Six cycles of R-CHOP-14 significantly improved event-free, progression-free, and overall survival over six cycles of CHOP-14 treatment. Response-adapted addition of chemotherapy beyond six cycles, though widely practiced, is not justified. Of the four regimens assessed in this study, six cycles of R-CHOP-14 is the preferred treatment for elderly patients, with which other approaches should be compared.

Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1)

BACKGROUND High-dose therapy (HDT) followed by transplantation of autologous haemopoietic stem cells is frequently done as part of first-line therapy in young patients with high-risk aggressive B-cell lymphoma. We investigated whether HDT with cytotoxic agents identical to those used for conventional therapy followed by autologous stem-cell transplantation (ASCT) improved survival outcome compared with conventional chemotherapy when rituximab was added to both modalities. METHODS We did an open-label, randomised trial comparing conventional chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) and rituximab (R-CHOEP-14) with dose-escalated sequential HDT and rituximab (R-MegaCHOEP) followed by repetitive ASCT in high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) patients aged 18-60 years with aggressive B-cell lymphoma. Eligible patients received radiotherapy for bulky, extranodal disease, or both. Randomisation (1:1) used the Pocock minimisation algorithm; patients were stratified by age-adjusted IPI factors, bulky disease, and centre. The primary endpoint was event-free survival. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00129090. FINDINGS 136 patients were randomly assigned to R-CHOEP-14 and 139 to R-MegaCHOEP. 130 patients in the R-CHOEP-14 group and 132 in the R-MegaCHOEP group were included in the intention-to-treat population. After a median of 42 months (IQR 29-59), 3-year event-free survival was 69·5% (95% CI 61·3-77·7) in the R-CHOEP-14 group and 61·4% (52·8-70·0) in the R-MegaCHOEP group (p=0·14; hazard ratio 1·3, 95% CI 0·9-2·0). All 128 evaluable patients treated with R-MegaCHOEP had grade 4 leucopenia, as did 48 (58·5%) of 82 patients with documented blood counts in the R-CHOEP-14 group. All 128 evaluable patients in the R-MegaCHOEP group had grade 3-4 thrombocytopenia, as did 26 (33·8%) of 77 patients in the R-CHOEP-14 group with documented blood counts. The most important non-haematological grade 3 or 4 adverse event was infection, which occurred in 96 (75·0%) of 128 patients treated with R-MegaCHOEP and in 40 (31·3%) of 128 patients treated with R-CHOEP-14. INTERPRETATION In young patients with high-risk aggressive B-cell lymphoma, R-MegaCHOEP was not superior to conventional R-CHOEP therapy and was associated with significantly more toxic effects. R-CHOEP-14 with or without radiotherapy remains a treatment option for these patients, with encouraging efficacy. FUNDING Deutsche Krebshilfe.

Beam properties and stability of a flattening-filter free 7 MV beam-an overview.

PURPOSE Several works have recently focused on flattening-filter-free (FFF) beams of linear accelerators of various companies (in particular, Varian and Elekta), but no overview as yet exists for the flattening-filter free 7XU beam (Siemens Artiste). METHODS Dosimetric properties of the 7XU beam were measured in May and September 2011. We present depth dose curves and beam profiles, output factors, and MLC transmission and assess the stability of the measurements. The 7XU beam was commissioned in the Pinnacle[superscript three] treatment planning system (TPS), and modeling results including the spectrum are presented. RESULTS The percent depth dose curve of the 7XU beam is similar to the flat 6X beam line, with a slightly smaller surface dose. The beam profiles show the characteristic shape of flattening-filter free beams, with deviations between measurements of generally less than 1%. The output factors of the 7XU beam decrease more slowly than for the 6X beam. The MLC transmission is comparable but slightly less for the 7XU beam. The 7XU beam can be adequately modeled by the Pinnacle[superscript three] TPS, with successful dosimetric verification. The spectrum of the 7XU beam has lower photon fluence up to approximately 2.5 MeV and higher fluence beyond, with a slightly higher mean energy. CONCLUSIONS The 7XU beam has been commissioned for clinical use after successful modeling, stability checks, and dosimetric verification.

Intraoperative radiotherapy (IORT) combined with external beam radiotherapy (EBRT) for soft-tissue sarcomas – a retrospective evaluation of the Homburg experience in the years 1995–2007

PurposeTo retrospectively evaluate the results after a regimen of surgery, IORT (intraoperative radiotherapy), and EBRT (external beam radiotherapy) for soft-tissue sarcomasMethods38 consecutive patients underwent IORT for soft-tissue sarcoma; 29 were treated for primary tumours, 9 for recurrences. There were 14 cases with liposarcomas, 8 with leiomyosarcomas, 7 with malignant fibrous histiocytomas. 27/38 tumours were located in the extremities, the remaining ones in the retroperitoneum or the chest. Radical resection was attempted in all patients; a R0-resection was achieved in 15/38 patients, R1 in 12/38 pats and R2 in 4/38 pats. IORT was performed using a J-125 source and a HDR (high dose rate) afterloading machine after suturing silicone flaps to the tumour bed. The total dose applied ranged from 8–15 Gy/0.5 cm tissue depth measured from the flap surface. After wound healing external beam radiotherapy (EBRT) was applied in 31/38 patients with total doses of 23–56 Gy dependent on resection status and wound situation. The mean duration of follow-up was 2.3 years.ResultsA local recurrence was found in 10/36 patients, lymph node metastases in 2/35, and distant metastases in 6/35 patients. The actuarial local control rate was 63%/5 years. The overall survival rate was 57%/5 years. There was no statistically significant difference between the results after treatment for primaries or for recurrences. Late toxicity to the skin was found in 13/31 patients, wound healing problems in 5/31 patients. A neuropathy was never seen.ConclusionThe combination of surgery, IORT, and EBRT yields favourable local control and survival data which are well within the range of the results reported in the literature. The complication rates, however, are considerable although the complications are not severe, they should be taken into account when therapy decisions are made.

Planning study and dose measurements of intracranial stereotactic radiation surgery with a flattening filter-free linac

PURPOSE Flattening filter-free (FFF) beams have recently become available for radiation therapy, offering much higher dose rates but complicating treatment owing to the nonflat profile. Stereotactic treatment is one of the most evident scenarios to investigate the use of FFF beams. METHODS AND MATERIALS We present a planning study of a FFF 7-MV beam for the treatment of brain metastases using multiple noncoplanar arcs. Plan differences as compared with flat 6 MV photon fields are estimated using different measures of quality. Absolute dosimetry and fluence distribution are verified and the out-of-field dose is measured. RESULTS The FFF 7-MV plans are slightly better than the flat 6-MV plans as evaluated by a number of quality indices, dose to organs at risk, and out-of-field dose, although differences may not be clinically relevant. Verification does not pose any problems. CONCLUSIONS The FFF 7-MV treatment plans are marginally superior to the flat-beam 6-MV plans in almost all cases, with greatly reduced treatment times (almost 50%).

Visualisation of Respiratory Tumour Motion and Co-Moving Isodose Lines in the Context of Respiratory Gating, IMRT and Flattening-Filter-Free Beams

Respiratory motion during percutaneous radiotherapy can be considered based on respiration-correlated computed tomography (4DCT). However, most treatment planning systems perform the dose calculation based on a single primary CT data set, even though cine mode displays may allow for a visualisation of the complete breathing cycle. This might create the mistaken impression that the dose distribution were independent of tumour motion. We present a movie visualisation technique with the aim to direct attention to the fact that the dose distribution migrates to some degree with the tumour and discuss consequences for gated treatment, IMRT plans and flattening-filter-free beams. This is a feasibility test for a visualisation of tumour and isodose motion. Ten respiratory phases are distinguished on the CT, and the dose distribution from a stationary IMRT plan is calculated on each phase, to be integrated into a movie of tumour and dose motion during breathing. For one example patient out of the sample of five lesions, the plan is compared with a gated treatment plan with respect to tumour coverage and lung sparing. The interplay-effect for small segments in the IMRT plan is estimated. While the high dose rate, together with the cone-shaped beam profile, makes the use of flattening-filter-free beams more problematic for conformal and IMRT treatment, it can be the option of choice if gated treatment is preferred. The different effects of respiratory motion, dose build-up and beam properties (segments and flatness) for gated vs. un-gated treatment can best be considered if planning is performed on the full 4DCT data set, which may be an incentive for future developments of treatment planning systems.

Should I Stay or Should I Go? A Prospective, Blinded Study Comparing the Diagnostic Capability of Dynamic and Stationary Pedobarography in Plantar Fasciitis

ABSTRACT The aim of this study was to determine the diagnostic capability of a dynamic gait analysis insole and compare its ability to detect clinical correlations to a common stationary analysis tool. Twenty‐five patients with chronic plantar fasciitis were included in this prospective, blinded, diagnostic study. Conventional, stationary gait analysis on a force plate on an even surface and continuous dynamic pedobarography on a standardized course consisting of different gait tasks were performed and correlated to the disease severity. Mean patient age was 53.6 (range 41 to 68) years, with a mean pain level of 6.1 (range 4 to 10) on the Visual Analogue Scale and a calcaneodynia score of 48.7 (range 33 to 66). Significant correlations were seen between several dynamic gait values and clinical scoring: cadence (rs = 0.56, p = .004), stance time (rs = –0.6, p = .002), center‐of‐pressure velocity (rs = 0.44, p = .046), and double support time (rs = 0.42, p = .042). No significant correlations were seen between any force plate gait analysis values and clinical scoring. In this study setting, dynamic gait analysis was able to identify clinically relevant correlations to plantar fasciitis disease severity that standard force plate measurements could not. &NA; Level of Clinical Evidence: 3