Matthias Hipp

Multicenter Phase II Trial of Chemoradiation With Oxaliplatin for Rectal Cancer

PURPOSE To evaluate the activity and safety of preoperative radiotherapy (RT) and concurrent capecitabine and oxaliplatin (XELOX-RT) plus four cycles of adjuvant XELOX in patients with rectal cancer. PATIENTS AND METHODS One hundred ten patients with T3/T4 or N+ rectal cancer were entered onto the trial in 11 investigator sites and received preoperative RT (50.4 Gy in 28 fractions). Capecitabine was administered concurrently at 1,650 mg/m2 on days 1 to 14 and 22 to 35, and oxaliplatin was administered at 50 mg/m2 on days 1, 8, 22, and 29. Surgery was scheduled 4 to 6 weeks after completion of XELOX-RT. Four cycles of adjuvant XELOX (capecitabine 1,000 mg/m2 bid on days 1 to 14; oxaliplatin 130 mg/m2 on day 1) were administered. The main end points were activity as assessed by the pathologic complete response (pCR) rate and the feasibility of postoperative XELOX chemotherapy. RESULTS After XELOX-RT, 103 of 104 eligible patients underwent surgery; pCR was achieved in 17 patients (16%), one patient had ypT0N1 disease, and 53 patients showed tumor regression of more than 50% of the tumor mass. R0 resections were achieved in 95% of patients, and sphincter preservation was accomplished in 77%. Full-dose preoperative XELOX-RT was administered in 96%. Grade 3 or 4 diarrhea occurred in 12% of patients. Postoperative complication occurred in 43% of patients. Sixty percent of patients received all four cycles of adjuvant XELOX, with sensory neuropathy (18%) and diarrhea (12%) being the main grade 3 or 4 toxicities. CONCLUSION Preoperative XELOX-RT plus four cycles of adjuvant XELOX is an active and feasible treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based treatment with XELOX- based multimodality treatment.

Dysphagia. Impact on quality of life after radio(chemo)therapy of head and neck cancer.

BACKGROUND In the past, xerostomia was considered one of the most important determining factors of quality of life (QoL) after radiotherapy (RT) of the head and neck region. In addition, more recent studies have shown that RT-induced dysphagia has an essential influence on the QoL. PATIENTS AND METHODS Between September 2005 and August 2007, 35 patients with locally advanced squamous cell carcinoma of the head and neck region were included in the prospective study. Patients were treated by IMAT (intensity-modulated arc therapy) or IMRT (intensity-modulated radiotherapy) planned on 3D imaging. A total of 28 patients (80%) received concomitant chemotherapy. The evaluation of QoL (EORTC QLQ-C30, H&N C-35) and toxicities (CTC 2.0) were assessed at the beginning of, during, and after RT as well as up to 12 months after the end of therapy. RESULTS At the end of therapy, 86% of the patients experienced difficulties in swallowing (62% CTC II-III°). Twelve months after the end of treatment, 15% still suffered from dysphagia CTC II-III°. Concomitant chemotherapy exacerbated the incidence and gravity of dysphagia, resulting in increasing dietary problems. QoL (EORTC) was significantly affected by dysphagia. In particular, the global state of health and QoL were influenced at the end of treatment (p=0.033) and at a later stage (p=0.050). CONCLUSION The findings of this study suggest that more emphasis should be placed on structured clinical diagnostics, therapy, and rehabilitation of deglutition problems. This means in particular to not only spare the parotids while planning the irradiation, but also to take into consideration the important structures for deglutition, like the retropharyngeal muscles.

Effects of Radiotherapy for Brain Metastases on Quality of Life (QoL)

Background:Prospective data on quality-of-life (QoL) effects of radiotherapy for brain metastases are currently lacking, but would be of great interest to guide therapeutic decisions.Patients and Methods:From 01/2007 to 08/2007, 46 patients with previously untreated brain metastases were recruited at eight centers. QoL was measured at start of treatment (T0) and at 3 months (T3mo). In the pilot study, two combinations of QoL instruments could be used at the discretion of the centers (A: EORTC QLQ-C30 and B: EORTC QLQ-C15-PAL both with brain module BN20, assessment by proxies with A: Palliative Care Outcome Scale, B: self-constructed brain-specific instrument).Results:All patients received whole-brain radiotherapy, four with an additional boost irradiation. At T3mo, 26/46 patients (56.5%) had died. 17/20 survivors (85%) completed the questionnaires. In 3-month survivors, QoL deteriorated in most domains, significant in drowsiness, hair loss and weakness of legs. The scores for headaches and seizures were slightly better after 3 months. Assessment by proxies also suggested worsening of QoL. Initial QoL at T0 was better in those alive than in those deceased at T3mo, significant for physical function and for the symptom scales of fatigue and pain, motor dysfunction, communication deficit and weakness of legs.Conclusion:Practicability and compliance appeared better with the (shorter) version B. This version is now used in the ongoing main phase of the study with additional centers. First results indicate a moderate worsening of QoL during the first 3 months after start of palliative radiotherapy for brain metastases. QoL at initiation of radiotherapy may be prognostic for survival.Hintergrund:Prospektive Daten über die Auswirkung einer palliativen Strahlentherapie auf die Lebensqualität (LQ) von Patienten mit Hirnmetastasen existieren nur wenige, jedoch sind sie von großem Interesse für Therapieentscheidungen.Patienten und Methodik:Von 01/2007 bis 08/2007 wurden an acht Zentren 46 Patienten mit bisher unbehandelten Hirnmetastasen rekrutiert (Tabelle 1). Die LQ vor und 3 Monate nach palliativer Strahlentherapie wurde erhoben. In der Pilotphase konnten die Zentren zwischen zwei Kombinationen von Instrumenten wählen (A: EORTC QLQ-C30 und B: QLQ C15-PAL jeweils mit Hirnmodul BN20, Fremdeinschätzung durch Angehörige mittels A: Palliative Care Outcome Scale, B: eigenen Hirnmoduls).Ergebnisse:Alle Patienten erhielten eine Ganzhirnbestrahlung, vier Patienten zusätzlich eine Boostbestrahlung. 3 Monate nach Therapiebeginn waren 26/46 Patienten (56,5%) verstorben. Die Rücklaufquote der Fragebögen der Überlebenden betrug 17/20 (85%). Für dieses Kollektiv der 3-Monats-Überlebenden zeigte die Selbsteinschätzung eine Verschlechterung in den meisten Bereichen, signifikant für Schläfrigkeit, Alopezie und Beinschwäche. Die Scores für Kopfschmerzen und Krampfleiden waren nach 3 Monaten etwas besser (Abbildung 1). Die Fremdeinschätzungen zeigten ebenfalls eine zunehmende Beeinträchtigung der Patienten nach 3 Monaten (Abbildung 2). Die initiale LQ war bei den 3-Monats-Überlebenden (Abbildung 3a) im Vergleich zu den Verstorbenen besser, signifikant für die körperliche Funktion und für die Symptomskalen Fatigue, Schmerz (Abbildung 3b), motorische Dysfunktion, Kommunikationsdefizit und Beinschwäche (Abbildung 3c).Schlussfolgerung:Die kürzere Fragebogenvariante B schien bezüglich der Praktikabilität und Compliance besser zu sein. Demzufolge wird diese Variante in der aktuell laufenden Hauptphase mit zusätzlichen Zentren verwendet (Abbildung 4). Erste Ergebnisse deuten auf eine mäßige LQ-Verschlechterung bei 3-Monats-Überlebenden hin. Möglicherweise könnte die initiale objektivierte LQ als prädiktiver Faktor herangezogen werden.

PREOPERATIVE RADIOTHERAPY OF ADVANCED RECTAL CANCER WITH CAPECITABINE AND OXALIPLATIN WITH OR WITHOUT CETUXIMAB: A POOLED ANALYSIS OF THREE PROSPECTIVE PHASE I-II TRIALS

PURPOSE A pooled analysis of three prospective trials of preoperative radiochemotherapy (RCT) for rectal cancer by using oxaliplatin and capecitabine with or without cetuximab was performed to evaluate the impact of additional cetuximab on pathologic complete response (pCR) rates and tumor regression (TRG) grades. METHODS AND MATERIALS Of 202 patients, 172 patients met the inclusion criteria (primary tumor stage II/III, M0). All patients received concurrent RCT, and 46 patients received additional cetuximab therapy. A correlation of pretreatment clinicopathologic factors and cetuximab treatment with early pCR rates (TRG > 50%) was performed with univariate and multivariate analyses. Toxicity data were recorded for all patients. RESULTS Of 172 patients, 24 (14%) patients achieved a pCR, and 84 of 172 (71%) patients showed a TRG of >50% in the surgical specimen assessment after preoperative treatment. Age, gender, and T/N stages, as well as localization of the tumor, were not associated with pCR or good TRG. The pCR rate was 16% after preoperative RCT alone and 9% with concurrent cetuximab therapy (p = 0.32). A significantly reduced TRG of >50% was found after RCT with cetuximab compared to RCT alone (p = 0.0035). This was validated by a multivariate analysis with all available clinical factors (p = 0.0037). Acute toxicity and surgical complications were not increased with additional cetuximab. CONCLUSIONS Triple therapy with RCT and cetuximab seems to be feasible, with no unexpected toxicity. Early response assessment (TRG), however, suggests subadditive interaction. A longer follow-up (and finally randomized trials) is needed to draw any firm conclusions with respect to local and distant failure rates.

Fistula-associated anal adenocarcinoma in Crohn's disease

Background: Adenocarcinoma arising from perianal fistulae in patients with Crohns disease (CD) is rare. The literature consists mainly of case reports and small series making characterization of this clinical entity difficult. We present 6 patients with CD and fistula‐associated anal adenocarcinoma (FAAA) and a systematic review of published series. Methods: Retrospective charts were reviewed of 6 consecutive patients with FAAA in CD treated from 1992 through 2007. All available variables of our patients and of all available published cases were included for statistical analysis. Results: All patients treated at our institution had severe perianal CD at presentation. The average age at time of diagnosis was 45.5 years. All patients underwent abdominoperineal resection (APR) and 4 received chemoradiation. Four patients died with metastatic disease, 1 is alive with pelvic recurrence at 55 months, and 1 is alive without evidence of disease at 19 months follow‐up. A total of 23 publications including 65 patients (37 female, mean age 53 years) with FAAA were reviewed in our systematic review. The average fistula duration was 14 years. Mean delay of cancer diagnosis was 11 months. APR was performed in 56 patients with an overall 3‐year survival rate of 54%. Thirteen of 15 patients with node‐positive tumors died with recurrent disease following surgery. Conclusions: Adenocarcinoma arising from long‐standing perianal CD fistulae is being increasingly reported. The outcome is poor following operative treatment, especially if perirectal lymph nodes are involved. Periodical cancer surveillance should be performed in all patients with long‐standing perianal CD fistulae. Inflamm Bowel Dis 2010

Effects of radiotherapy for brain metastases on quality of life (QoL). Prospective pilot study of the DEGRO QoL working party.

Background:Prospective data on quality-of-life (QoL) effects of radiotherapy for brain metastases are currently lacking, but would be of great interest to guide therapeutic decisions.Patients and Methods:From 01/2007 to 08/2007, 46 patients with previously untreated brain metastases were recruited at eight centers. QoL was measured at start of treatment (T0) and at 3 months (T3mo). In the pilot study, two combinations of QoL instruments could be used at the discretion of the centers (A: EORTC QLQ-C30 and B: EORTC QLQ-C15-PAL both with brain module BN20, assessment by proxies with A: Palliative Care Outcome Scale, B: self-constructed brain-specific instrument).Results:All patients received whole-brain radiotherapy, four with an additional boost irradiation. At T3mo, 26/46 patients (56.5%) had died. 17/20 survivors (85%) completed the questionnaires. In 3-month survivors, QoL deteriorated in most domains, significant in drowsiness, hair loss and weakness of legs. The scores for headaches and seizures were slightly better after 3 months. Assessment by proxies also suggested worsening of QoL. Initial QoL at T0 was better in those alive than in those deceased at T3mo, significant for physical function and for the symptom scales of fatigue and pain, motor dysfunction, communication deficit and weakness of legs.Conclusion:Practicability and compliance appeared better with the (shorter) version B. This version is now used in the ongoing main phase of the study with additional centers. First results indicate a moderate worsening of QoL during the first 3 months after start of palliative radiotherapy for brain metastases. QoL at initiation of radiotherapy may be prognostic for survival.Hintergrund:Prospektive Daten über die Auswirkung einer palliativen Strahlentherapie auf die Lebensqualität (LQ) von Patienten mit Hirnmetastasen existieren nur wenige, jedoch sind sie von großem Interesse für Therapieentscheidungen.Patienten und Methodik:Von 01/2007 bis 08/2007 wurden an acht Zentren 46 Patienten mit bisher unbehandelten Hirnmetastasen rekrutiert (Tabelle 1). Die LQ vor und 3 Monate nach palliativer Strahlentherapie wurde erhoben. In der Pilotphase konnten die Zentren zwischen zwei Kombinationen von Instrumenten wählen (A: EORTC QLQ-C30 und B: QLQ C15-PAL jeweils mit Hirnmodul BN20, Fremdeinschätzung durch Angehörige mittels A: Palliative Care Outcome Scale, B: eigenen Hirnmoduls).Ergebnisse:Alle Patienten erhielten eine Ganzhirnbestrahlung, vier Patienten zusätzlich eine Boostbestrahlung. 3 Monate nach Therapiebeginn waren 26/46 Patienten (56,5%) verstorben. Die Rücklaufquote der Fragebögen der Überlebenden betrug 17/20 (85%). Für dieses Kollektiv der 3-Monats-Überlebenden zeigte die Selbsteinschätzung eine Verschlechterung in den meisten Bereichen, signifikant für Schläfrigkeit, Alopezie und Beinschwäche. Die Scores für Kopfschmerzen und Krampfleiden waren nach 3 Monaten etwas besser (Abbildung 1). Die Fremdeinschätzungen zeigten ebenfalls eine zunehmende Beeinträchtigung der Patienten nach 3 Monaten (Abbildung 2). Die initiale LQ war bei den 3-Monats-Überlebenden (Abbildung 3a) im Vergleich zu den Verstorbenen besser, signifikant für die körperliche Funktion und für die Symptomskalen Fatigue, Schmerz (Abbildung 3b), motorische Dysfunktion, Kommunikationsdefizit und Beinschwäche (Abbildung 3c).Schlussfolgerung:Die kürzere Fragebogenvariante B schien bezüglich der Praktikabilität und Compliance besser zu sein. Demzufolge wird diese Variante in der aktuell laufenden Hauptphase mit zusätzlichen Zentren verwendet (Abbildung 4). Erste Ergebnisse deuten auf eine mäßige LQ-Verschlechterung bei 3-Monats-Überlebenden hin. Möglicherweise könnte die initiale objektivierte LQ als prädiktiver Faktor herangezogen werden.

Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases

BackgroundRecently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information.MethodsFrom 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months.ResultsAt 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival.ConclusionsModerate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information.

Searching standard parameters for volumetric modulated arc therapy (VMAT) of prostate cancer

BackgroundSince December 2009 a new VMAT planning system tool is available in Oncentra® MasterPlan v3.3 (Nucletron B.V.). The purpose of this study was to work out standard parameters for the optimization of prostate cancer.MethodsFor ten patients with localized prostate cancer plans for simultaneous integrated boost were optimized, varying systematically the number of arcs, collimator angle, the maximum delivery time, and the gantry spacing. Homogeneity in clinical target volume, minimum dose in planning target volume, median dose in the organs at risk, maximum dose in the posterior part of the rectum, and number of monitor units were evaluated using student’s test for statistical analysis. Measurements were performed with a 2D-array, taking the delivery time, and compared to the calculation by the gamma method.ResultsPlans with collimator 45° were superior to plans with collimator 0°. Single arc resulted in higher minimum dose in the planning target volume, but also higher dose values to the organs at risk, requiring less monitor units per fraction dose than dual arc. Single arc needs a higher value (per arc) for the maximum delivery time parameter than dual arc, but as only one arc is needed, the measured delivery time was shorter and stayed below 2.5 min versus 3 to 5 min. Balancing plan quality, dosimetric results and calculation time, a gantry spacing of 4° led to optimal results.ConclusionA set of parameters has been found which can be used as standard for volumetric modulated arc therapy planning of prostate cancer.

Clostridium difficile-associated diarrhea in radiooncology: an underestimated problem for the feasibility of the radiooncological treatment?

Background and PurposeOver the last years an increasing incidence of Clostridium difficile-associated diarrhea (CDAD) has been reported. Especially haematology-oncology patients are at risk of developing CDAD.The aim of this analysis is to determine the incidence of CDAD in radiooncological patients and to find out what relevance CDAD has for the feasibility of the radiooncological treatment, as well as to detect and describe risk factors.Patients and MethodsIn a retrospective analysis from 2006 to 2010 34 hospitalized radiooncological patients could be identified having CDAD. The risk factors of these patients were registered, the incidence was calculated and the influence on the feasibility of the radiooncological therapy was evaluated. Induced arrangements for prophylaxis of CDAD were identified and have been correlated with the incidence.ResultsThe incidence of CDAD in our collective is 1,6%. Most of the patients suffering from a CDAD were treated for carcinoma in the head and neck area. Common risk factors were antibiotics, proton pump inhibitors, cytostatic agents and tube feeding.Beside a high rate of electrolyte imbalance and hypoproteinemia a decrease of general condition was frequent. 12/34 patients had a prolonged hospitalization, in 14/34 patients radiotherapy had to be interrupted due to CDAD. In 21 of 34 patients a concomitant chemotherapy was planned. 4/21 patients could receive all of the planned cycles and only 2/21 patients could receive all of the planned cycles in time.4/34 patients died due to CDAD. In 4/34 patients an initially curative treatment concept has to be changed to a palliative concept.With intensified arrangements for prophylaxis the incidence of CDAD decreased from 4,0% in 2007 to 0,4% in 2010.ConclusionThe effect of CDAD on the feasibility of the radiotherapy and a concomitant chemotherapy is remarkable. The morbidity of patients is severe with a high lethality.Reducing of risk factors, an intense screening and the use of probiotics as prophylaxis can reduce the incidence of CDAD.

IMRT of prostate cancer: a comparison of fluence optimization with sequential segmentation and direct step-and-shoot optimization.

Background and Purpose:Intensity-modulated radiation therapy (IMRT) has shown its superiority to three-dimensional conformal radiotherapy in the treatment of prostate cancer. Different optimization algorithms are available: algorithms which first optimize the fluence followed by a sequencing (IM), and algorithms which involve the machine parameters directly in the optimization process (DSS). The aim of this treatment-planning study is to compare both of them regarding dose distribution and treatment time.Patients and Methods:Ten consecutive patients with localized prostate cancer were enrolled for the planning study. The planning target volume and the rectum volume, urinary bladder and femoral heads as organs at risk were delineated. Average doses, the target dose homogeneity H, D5, D95, monitor units per fraction, and the number of segments were evaluated.Results:While there is only a small difference in the mean doses at rectum and bladder, there is a significant advantage for the target dose homogeneity in the DSS-optimized plans compared to the IM-optimized ones. Differences in the monitor units (nearly 10% less for DSS) and the number of segments are also statistically significant and reduce the treatment time.Conclusion:Particularly with regard to the tumor control probability, the better homogeneity of the DSS-optimized plans is more profitable. The shorter treatment time is an improvement regarding intrafractional organ motion. The DSS optimizer results in a higher target dose homogeneity and, simultaneously, in a lower number of monitor units. Therefore, it should be preferred for IMRT of prostate cancer.Hintergrund und Ziel:Die intensitätsmodulierte Strahlentherapie (IMRT) hat ihre Überlegenheit gegenüber der dreidimensionalen konformalen Strahlentherapie in der Behandlung des Prostatakarzinoms gezeigt. Verschiedene Optimierungsalgorithmen stehen zur Verfügung: Algorithmen, die erst die Fluenz optimieren und anschließend eine Segmentierung durchführen (IM), und Algorithmen, die die Maschinenparameter direkt in den Optimierungsprozess integrieren (DSS). Ziel dieser Planungsstudie ist es, beide hinsichtlich Dosisverteilung und Bestrahlungszeit zu vergleichen.Patienten und Methodik:In die Planungsstudie wurden zehn aufeinanderfolgende Patienten mit lokalisiertem Prostatakarzinom eingeschlossen. Das Planungszielvolumen und als Risikostrukturen das Rektumvolumen, Harnblase und beide Femurköpfe wurden markiert. Die durchschnittliche Dosis in den Risikoorganen, die Homogenität im Zielvolumen, D5, D95, die Monitoreinheiten pro Fraktion und die mittlere Segmentzahl wurden ermittelt.Ergebnisse:Während nur ein kleiner Unterschied in der mittleren Dosis in Rektum und Blase besteht, findet sich ein signifikanter Vorteil bezüglich der Homogenität im Zielvolumen für die mit „direct step and shoot“ optimierten Pläne gegenüber denjenigen mit Fluenzoptimierung. Die Unterschiede bei den Monitoreinheiten (fast 10% weniger für den DSS-optimierten Plan) und der Segmentzahl sind ebenfalls statistisch signifikant.Schlussfolgerung:Insbesondere im Hinblick auf die Tumorkontrollwahrscheinlichkeit ist die größere Homogenität der DSS-optimierten Pläne vorteilhafter. Die kürzere Behandlungszeit stellt eine Verbesserung in Bezug auf intrafraktionelle Organbewegung dar. Der DSS-Optimierer führt zu einer besseren Homogenität im Zielvolumen bei einer reduzierten Anzahl von Monitoreinheiten. Deshalb sollte er für die IMRT des Prostatakarzinoms bevorzugt werden.