Thomas Feyerabend

Randomized phase III trial of postoperative radiochemotherapy +/- amifostine in head and neck cancer. Is there evidence for radioprotection?

Purpose: Experimental and clincial data suggest a reduction of radiation-induced acute toxicity by amifostine (A). We investigated this issue in a randomized trial comparing radiochemotherapy (RT + CT) versus radiochemotherapy plus amifostine (RC + CT + A) in patients with head and neck cancer. Patients and Methods: 56 patients with oro-/hypopharynx or larynx cancer (T1–2 N1–2 G3, T3–4 N0–2 G1–3) were randomized to receive RC + CT alone or RC + CT + A. Patients were irradiated up to 60 Gy (R0) or 70 Gy (R1/2) and received chemotherapy (70 mg/m2 carboplatin, day 1–5 in week 1 and 5 of radiotherapy). 250 mg amifostine were applied daily before each radiotherapy session. Acute toxicity was evaluated according to the Common Toxicity Criteria (CTC). As for acute xerostomia, patients with laryngeal cancer were excluded from evaluation. Results: 50 patients were evaluable (25 patients in the RC + CT, 25 patients in the RC + CT + A group). Clinical characteristics were well balanced in both treatment groups. Amifostine provided reduction in acute xerostomia and mucositis but had no obvious influence on Karnofsky performance status, body weight, cutaneous side effects, and alopecia. The differences between both groups were statistically significant for acute xerostomia and nonsignificant, but with a trend for mucositis. Conclusions: According to our results, there is a radioprotective effect on salivary glands and a potential effect on oral mucosa by amifostine in postoperative radiotherapy combined with carboplatin. To improve the radio- and chemoprotective effects of amifostine in clinical practice, the application of a higher dose (> 250 mg) seems to be necessary.Hintergrund: Experimentelle und klinische Daten legen eine Reduktion der akuten radiogenen Nebenwirkungen durch Amifostin (A) nahe. Wir untersuchten diese Frage in einer randomisierten Studie mit dem Vergleich von Radiochemotherapie (RC + CT) versus Radiochemotherapie + Amifostin (RC + CT + A) bei HNO-Tumorpatienten. Patienten und Methodik: 56 Patienten mit Oro-/Hypopharynx- oder Larynxkarzinom (T1–2 N1–2 G3, T3–4 N0–2 G1–3) wurden randomisiert behandelt. Sie wurden mit 60 Gy (R0) oder 70 Gy (R1/2) bestrahlt und erhielten Zytostatika (70 mg/m2 Carboplatin, Tag 1–5 in Woche 1 und 5 der Radiatio). Vor jeder Strahlentherapiesitzung wurden ggf. 250 mg Amifostin appliziert. Die akuten Nebenwirkungen wurden nach den CTC-Kriterien bewertet. Bezüglich der Xerostomie wurden die Larynxkarzinompatienten von der Analyse ausgeschlossen. Ergebnisse: 50 Patienten waren auswertbar (25 Patienten mit RC + CT, 25 Patienten mit RC + CT + A). Die klinischen Parameter waren in beiden Gruppen sehr ähnlich. Amifostin reduzierte die Xerostomie und die Mukositis, hatte aber keinen Einfluss auf den Leistungszustand, das Körpergewicht, kutane Nebenwirkungen und Alopezie. Die Unterschiede zwischen beiden Gruppen waren statistisch signifikant bezüglich der Xerostomie, nicht jedoch für die Mukositis, wenn auch ein Trend zugunsten der Amifostin-Gruppe vorhanden war. Schlussfolgerungen: Wir sahen einen radioprotektiven Effekt von Amifostin auf die Speicheldrüsen und einen möglichen Effekt auf die Mundhöhlenschleimhaut bei einer postoperativen Radiochemotherapie mit Carboplatin. Um die radio- und chemoprotektive Wirkung von Amifostin klinisch zu verbessern, müssen vermutlich höhere Dosen als 250 mg verwendet werden.

Randomized Phase III Trial of Postoperative Radiochemotherapy ± Amifostine in Head and Neck Cancer

Purpose: Experimental and clincial data suggest a reduction of radiation-induced acute toxicity by amifostine (A). We investigated this issue in a randomized trial comparing radiochemotherapy (RT + CT) versus radiochemotherapy plus amifostine (RC + CT + A) in patients with head and neck cancer. Patients and Methods: 56 patients with oro-/hypopharynx or larynx cancer (T1–2 N1–2 G3, T3–4 N0–2 G1–3) were randomized to receive RC + CT alone or RC + CT + A. Patients were irradiated up to 60 Gy (R0) or 70 Gy (R1/2) and received chemotherapy (70 mg/m2 carboplatin, day 1–5 in week 1 and 5 of radiotherapy). 250 mg amifostine were applied daily before each radiotherapy session. Acute toxicity was evaluated according to the Common Toxicity Criteria (CTC). As for acute xerostomia, patients with laryngeal cancer were excluded from evaluation. Results: 50 patients were evaluable (25 patients in the RC + CT, 25 patients in the RC + CT + A group). Clinical characteristics were well balanced in both treatment groups. Amifostine provided reduction in acute xerostomia and mucositis but had no obvious influence on Karnofsky performance status, body weight, cutaneous side effects, and alopecia. The differences between both groups were statistically significant for acute xerostomia and nonsignificant, but with a trend for mucositis. Conclusions: According to our results, there is a radioprotective effect on salivary glands and a potential effect on oral mucosa by amifostine in postoperative radiotherapy combined with carboplatin. To improve the radio- and chemoprotective effects of amifostine in clinical practice, the application of a higher dose (> 250 mg) seems to be necessary.Hintergrund: Experimentelle und klinische Daten legen eine Reduktion der akuten radiogenen Nebenwirkungen durch Amifostin (A) nahe. Wir untersuchten diese Frage in einer randomisierten Studie mit dem Vergleich von Radiochemotherapie (RC + CT) versus Radiochemotherapie + Amifostin (RC + CT + A) bei HNO-Tumorpatienten. Patienten und Methodik: 56 Patienten mit Oro-/Hypopharynx- oder Larynxkarzinom (T1–2 N1–2 G3, T3–4 N0–2 G1–3) wurden randomisiert behandelt. Sie wurden mit 60 Gy (R0) oder 70 Gy (R1/2) bestrahlt und erhielten Zytostatika (70 mg/m2 Carboplatin, Tag 1–5 in Woche 1 und 5 der Radiatio). Vor jeder Strahlentherapiesitzung wurden ggf. 250 mg Amifostin appliziert. Die akuten Nebenwirkungen wurden nach den CTC-Kriterien bewertet. Bezüglich der Xerostomie wurden die Larynxkarzinompatienten von der Analyse ausgeschlossen. Ergebnisse: 50 Patienten waren auswertbar (25 Patienten mit RC + CT, 25 Patienten mit RC + CT + A). Die klinischen Parameter waren in beiden Gruppen sehr ähnlich. Amifostin reduzierte die Xerostomie und die Mukositis, hatte aber keinen Einfluss auf den Leistungszustand, das Körpergewicht, kutane Nebenwirkungen und Alopezie. Die Unterschiede zwischen beiden Gruppen waren statistisch signifikant bezüglich der Xerostomie, nicht jedoch für die Mukositis, wenn auch ein Trend zugunsten der Amifostin-Gruppe vorhanden war. Schlussfolgerungen: Wir sahen einen radioprotektiven Effekt von Amifostin auf die Speicheldrüsen und einen möglichen Effekt auf die Mundhöhlenschleimhaut bei einer postoperativen Radiochemotherapie mit Carboplatin. Um die radio- und chemoprotektive Wirkung von Amifostin klinisch zu verbessern, müssen vermutlich höhere Dosen als 250 mg verwendet werden.

Local hyperthermia, radiation, and chemotherapy in recurrent breast cancer is feasible and effective except for inflammatory disease

PURPOSE To investigate the feasibility and effectiveness of radiochemothermotherapy (triple-modality therapy) in patients with inoperable recurrent breast cancer. PATIENTS AND METHODS Patients with inoperable recurrent lesions, World Health Organization (WHO) performance status of 2 or greater, life expectancy of more than 3 months, adequate bone marrow, hepatic and renal function were eligible for this Phase I/II study. Conventionally fractionated or hyperfractionated radiotherapy (RT) was performed. Once-weekly local hyperthermia (HT) combined with chemotherapy (CT; epirubicin 20 mg/m(2), ifosfamide 1.5 g/m(2)) was applied within 30 min after RT. RESULTS Twenty-five patients, all heavily pretreated (18/25 preirradiated), received a mean total dose of 49 Gy. The median number of HT/CT sessions was 4. Skin toxicity was low, whereas bone marrow toxicity was significant (leucopenia Grade 3/4 in 14/1 patients). The overall response rate was 80% with a complete response (CR) rate of 44%. Response rates in patients with noninflammatory disease (n = 14; CR 10 patients, partial response [PR] 3 patients) were far better than in patients with inflammatory disease (n = 11; CR 1 patient, PR 6 patients). CONCLUSIONS In patients with recurrent breast cancer, triple-modality therapy is feasible with acceptable toxicity. High remission rates can be achieved in noninflammatory disease, however, local control is limited to a few months. Whether the addition of chemotherapy has a clear-cut advantage to radiothermotherapy alone remains an open question.

TUMOR OXYGENATION AFTER RADIOTHERAPY, CHEMOTHERAPY, AND/OR HYPERTHERMIA PREDICTS TUMOR FREE SURVIVAL

PURPOSE To investigate the influence of different treatment modalities (radiotherapy, chemotherapy, and hyperthermia) on the oxygenation of human tumor xenografts and to correlate it with the tumoricidal effect we conducted this study. METHODS AND MATERIALS Human-derived head-and-neck squamous cell carcinoma xenografts (implanted in nude mice/nine groups of 10 mice) were treated with various treatment modalities and combinations of them (radiation with 5 x 2 or 10 x 2 Gy, hyperthermia at 41 degrees C or 41.8 degrees C, chemotherapy with ifosfamide [32 mg/kg] or cisplatin [2 mg/kg]). The tumor volume was evaluated 3 times per week until Day 60. Tumor pO(2) was measured at Day 1, 5, 8, and 12 with a polarographic pO(2) histograph. RESULTS Within treatment time (maximum, 10 days) the median pO(2) increased in all groups (except the control group), concomitantly the fraction of measurements of pO(2) that were less than 10 mm Hg showed a constant decrease (p < or = 0.001). The highest difference between the median pO(2) values and the fraction of measurements of pO(2) that were less than 10 mm Hg at the start and 1 week after the end of therapy occurred in the groups with radiochemothermotherapy (triple-modality therapy; p< or = 0.001). At Day 60, the highest rate of complete remissions was observed in the triple-modality therapy groups. CONCLUSION Tumor oxygenation under a single or combined cancer treatment is correlated with treatment efficacy in terms of complete remissions at Day 60. The posttherapeutic fraction of measurements of pO(2) that were less than 10 mm Hg correlates even better with the long term tumor free survival than the median pO(2) values or the pretherapeutic fraction of measurements of pO(2) that were less than 10 mm Hg.

Backscatter dose from metallic materials due to obliquely incident high-energy photon beams.

If metallic material is exposed to ionizing radiation of sufficient high energy, an increase in dose due to backscatter radiation occurs in front of this material. Our purpose in this study was to quantify these doses at variable distances between scattering materials and the detector at axial beam angles between 0 degree (zero angle in beams eye view) and 90 degrees. Copper, silver and lead sheets embedded in a phantom of perspex were exposed to 10 MV-bremsstrahlung. The detector we developed is based on the fluorescence property of pyromellitic acid (1,2,4,5 benzenetetracarboxylic acid) after exposure to ionizing radiation. Our results show that the additional doses and the corresponding dose distribution in front of the scattering materials depend quantitatively and qualitatively on the beam angle. The backscatter dose increases with varying beam angle from 0 degree to 90 degrees up to a maximum at 55 degrees for copper and silver. At angles of 0 degree and 55 degrees the integral backscatter doses over a tissue-equivalent depth of 2 mm are 11.2% and 21.6% for copper and 24% and 28% for silver, respectively. In contrast, in front of lead there are no obvious differences of the measured backscatter doses at angles between 0 degree and 55 degrees. With a further increase of the beam angle from 55 degrees to 90 degrees the backscatter dose decreases steeply for all three materials. In front of copper a markedly lower penetrating depth of the backscattered electrons was found for an angle of 0 degree compared to 55 degrees. This dependence from the beam angle was less pronounced in front of silver and not detectable in front of lead. In conclusion, the dependence of the backscatter dose from the angle between axial beam and scattering material must be considered, as higher scattering doses have to be considered than previously expected. This may have a clinical impact since the surface of metallic implants is usually curved.

Local hyperthermia, radiation, and chemotherapy in locally advanced malignancies.

Tumor size is a significant prognostic variable for attaining complete regression (CR) with local hyperthermia (HT) and radiation therapy (RT). The addition of weekly chemotherapy was evaluated to improve the efficacy of thermoradiotherapy in poor-prognosis lesions (i.e. > or = 7 cm2 or > or = 14 cm3) which have an expected CR rate of approximately 30 +/- 8%. Patients were entered into a two-arm phase-II study: arm 1 = breast cancer (10 patients), ifosfamide (1.5 g/m2) + epirubicin (20 mg/m2) + HT + RT; arm 2 = sarcoma (7 patients) and head and neck cancer (9 patients), cisplatin (40 mg/m2) + HT + RT. Therapy encompassing 106 triple-modality sessions was generally well tolerated for both arms; 2 instances of grade-3 and 1 of grade-4 (arm 2) local toxicity (WHO criteria) were observed. There were 4 instances of grade-3 myelosuppression (arm 1). The CR rates for arms 1 and 2 were 70 and 19%, respectively, suggesting that the combination of ifosfamide/epirubicin/HT/RT deserves further investigation in the context of localized breast cancer.

Spinale Metastasierung bei malignen Gliomen

PURPOSE Extracranial metastases of malignant gliomas are rare. We report 2 cases with spinal metastases in patients suffering from glioma. PATIENTS AND METHOD Two patients (33 and 57 years old) developed spinal canal metastases of a glioblastoma multiforme and anaplastic astrocytoma Grade III respectively 25 and 9 months after surgical resection and radiotherapy. Both metastases were confirmed pathohistologically. RESULTS Intraspinal metastases were irradiated with a total dose of 12.6 Gy and 50 Gy. Treatment withdrawal was necessary in one patient due to reduced clinical condition. Regression of neurological symptoms was observed in the second patient. CONCLUSIONS Spinal spread of malignant glioma should be considered during care and follow-up in glioma patients with spinal symptoms.ZusammenfassungHintergrundMaligne Gliome metastasieren äußerst selten extrakraniell. Wir stellen zwei Fälle einer spinalen Filialisierung bei Gliompatienten vor.Patientengut und MethodeZwei Patienten (33 und 57 Jahre alt) entwickelten 25 bzw. neun Monate nach Resektion und postoperativer Radiatio eines Glioblastoma multiforme und eines anaplastischen Astrozytoms WHO-Grad III histologisch gesicherte intraspinale Metastasen, welche durch Sensibilitätsstörungen der Beine symptomatisch wurden.ErgebnisseDie intraspinalen Filiae wurden mit 12,6 Gy bzw. 50 Gy bestrahlt. Bei einem Patienten mußte die Radiatio wegen zunehmender Verschlechterung des Allgemeinzustandes, abgebrochen werden bei dem zweiten Patienten besserte sich die neurologische Symptomatik.SchlußfolgerungBei der Betreuung von Gliompatienten sollte, insbesondere in der Nachsorge, an die Möglichkeit der spinalen Metastasierung mit entsprechender Symptomatik gedacht werden.AbstractPurposeExtracranial metastases of malignant gliomas are rare. We report 2 cases with spinal metastases in patients suffering from glioma.Patients and MethodTwo patients (33 and 57 years old) developed spinal canal metastases of a glioblastoma multiforme and anaplastic astrocytoma Grade III respectively 25 and 9 months after surgical resection and radiotherapy. Both metastases were confirmed pathohistologically.ResultsIntraspinal metastases were irradiated with a total dose of 12.6 Gy and 50 Gy. Treatment withdrawal was necessary in one patient due to reduced clinical condition. Regression of neurological symptoms was observed in the second patient.ConclusionsSpinal spread of malignant glioma should be considered during care and follow-up in glioma patients with spinal symptoms.

Clinical use of a simulation-multileaf collimator

BackgroundAt the University of Lübeck, radiotherapy is delivered by a 6/18-MV linear accelerator. Using the integrated multileaf collimator, irradiation of individually shaped treatment fields is possible in place of alloy blocks. Due to unsatisfactory pretherapeutic review of the radiation-field-specific multileaf collimator (MLC) configuration, we developed a simulation-multileaf collimator (SMLC) and assessed its feasibility at different tumor sites.Material and MethodsThe SMLC is made of a perspex carrier with 52 horizontal sliding leaves. The position of each leaf is calculated by a 3D treatment-planning computer. The technician manually adjusts the leaves according to the beams-eye-view plot of the planning computer. Consequently, the SMLC is mounted on the therapy simulator at a distance of 64.8 cm from the focus. The treatment fields and the position of the leaves are documented by X-ray films.ResultsUsing the SMLC, radiation oncologists are able to review exactly the leaf configuration of each MLC-shaped radiation field and to correlate the MLC-shaped radiation field with the treated volume, the organs at risk and the port films acquired by the Portal Vision® system.ConclusionThe SMLC is a new tool to review radiation planning that uses an MLC in daily routine. The use of the SMLC improves the documentation and the quality assurance. It accelerates the treatment field review at the linear accelerator by comparing the SMLC simulator films with the portal images.ZusammenfassungHintergrundSeit 1994 werden Patienten an der Lübecker Universitätsklinik für Strahlentherapie und Nuklearmedizin an einem Linearbeschleuniger bestrahlt, der mit einem Multileaf-Kollimator ausgerüstet ist. Dieser ermöglicht die Bestrahlung individuel geformter Zielvolumina ohne gegossene Individualsatelliten. Wegen der unzureichenden prätherapeutischen Kontrolle der Lamellenkonfiguration des Multileaf-Kollimators wurde ein Simulations-Multileaf-Kollimator (SMLC) entwickelt und dessen Anwendbarkeit bei verschiedenen Tumorlokalisationen überprüft.Material und Methode nDer Simulations-Multileaf-Kollimator besteht aus einem Plexiglasträger mit 52 horizontal beweglichen Lamellen. Die Position jeder einzelnen Lamelle wird vom 3D-Planungscomputer berechnet. Die Lamellen werden entsprechend dem Beams-Eye-View-Ausdruck des Planungsrechners manuell eingestellt. Anschließend wird der Simulations-Multileaf-Kollimator in einem Abstand von 64,8 cm vom Fokus des Simulators in den Strahlengang eingeschoben. Die Bestrahlungsfelder und die Lamellenkonfiguration werden mit Röntgenfilmen dokumentiert.ErgebnisseDer Strahlentherapeut kann mit Hilfe des Simulations-Multileaf-Kollimators die Lamellenkonfiguration MLC-konfigurierter Bestrahlungsfelder exakt beurteilen und diese mit den Portal-Imaging-Verifikationsaufnahmen korrelieren.SchlußfolgerungDer neu entwickelte Simulations-Multileaf-Kollimator ermöglicht in der täglichen Routine der Therapiesimulation die sichere Kontrolle und Dokumentation der Lamellenkonfiguration des Multileaf-Kollimators. Die Kontrolle der Bestrahlungsfelder am Beschleuniger wird durch den Vergleich der SMLC-Röntgenfilme mit den Verifikationsaufnahmen beschleunigt.

Therapeutic outcome and side-effects after radiotherapy, chemotherapy and/or hyperthermia treatment of head and neck tumour xenografts

The aim of the study was to optimise the still unsatisfactory therapeutic results in head and neck cancer by studying the results and the side-effects of radiotherapy, chemotherapy and/or local hyperthermia treatment of human tumour xenografts. Mice carrying human-derived head and neck squamous cell carcinoma xenografts with a mean volume of 100 mm(3) received 5x2 Gy, cisplatin or ifosfamide and/or local hyperthermia at 41/41.8 degrees C. Haematocrit and tumour volumes were determined two or three times per week, respectively, until day 25 or day 60. At day 60, the highest number of complete remissions (CRs) (80%) was observed in the triple modality therapy group with radiation, local hyperthermia at 41.8 C and cisplatin at a dosage of 2 mg/kg body weight (b.w.). Therapeutic side-effects were moderate weight loss and a mild anaemia. Thus, with regard to the long-term tumour-free survival, the most effective treatment was the combination of radiotherapy, cisplatin and local hyperthermia at 41.8 C.

Stereologic evaluation of the vasculature in a MX1 xenotransplanted tumour model after combinations of treatment with ifosfamide, hyperthermia and irradiation.

The vascularization of tumours is a critical parameter of their growing and metastatic behaviour. However, little is known about the morphologic reactions of the microvasculature, especially the capillary bed of tumours and the adjacent tissue. In this study, the vessels in MX1 xenotransplants in athymic nu/nu nude mice were quantified and the angioarchitecture was visualized with the aim of presenting stereologic parameters of vessels based on a morphometric analysis of post mortem tissue blocks which were processed by standard histological procedures. In order to study changes of the microvasculature of MX1 tumours, the xenotransplanted nude mice were treated by different therapeutic regimens. Standardized hyperthermia, ifosfamide and irradiation therapies were applied. Special interest was focused on early changes of capillaries and of the pre- as well as post-terminal vascular bed. The stereologic evaluation of capillaries and larger vessels immediately after the therapy with ifosfamide and hyperthermia shows an increase of the mean capillary sizes. Furthermore, tumour samples after the 5th day of irradiation (5 x 2 Gy) and combinations of irradiation and chemotherapy treatment have been investigated. After 5 days of irradiation, a significant decrease of the vascular density was found. The results presented here clearly show that the timing and the mode of therapy influence the capillary morphology and periterminal vasculature of xenotransplanted MX1 tumours.