Felix Zwicker

IMRT reirradiation with concurrent cetuximab immunotherapy in recurrent head and neck cancer.

AbstractPurpose:In this retrospective investigation, the outcome and toxicity after reirradiation with concurrent cetuximab immunotherapy of recurrent head and neck cancer (HNC) in patients who had contraindications to platinum-based chemotherapy were analyzed.Materials and Methods:Ten patients with locally advanced recurrent HNC were retrospectively evaluated. In 9 cases, histology was squamous cell carcinoma, in one case adenoid cystic carcinoma. External beam radiotherapy was part of the initial treatment in all cases. Reirradiation was carried out using step-and-shoot intensity-modulated radiotherapy (IMRT) with a median dose of 50.4 Gy. Cetuximab was applied as loading dose (400 mg/m2) 1 week prior to reirradiation and then weekly concurrently with radiotherapy (250 mg/m2).Results:The median overall survival time after initiation of reirradiation was 7 months; the 1-year overall survival (OS) rate was 40%. Local failure was found in 3 patients, resulting in a 1-year local control (LC) rate of 61%. The 1-year locoregional control (LRC) rate was 44%, while the 1-year distant metastasis-free survival (DMFS) was 75%. Acute hematological toxicity was not observed in the group. Severe acute toxicity included one fatal infield arterial bleeding and one flap necrosis. Severe late toxicities were noted in 2 patients: fibrosis of the temporomandibular joint in 1 patient and stenosis of the cervical esophagus in another.Conclusions:IMRT reirradiation with concurrent cetuximab immunotherapy in recurrent HNC is feasible with acceptable acute toxicity. Further investigations are necessary to determine the clinical role of this therapy concept.ZusammenfassungZiel:In dieser Untersuchung analysierten wir Behandlungsergebnis und Toxizität nach kombinierter Re-Bestrahlung mit simultaner Cetuximab-Immuntherapie von rezidivierten HNO-Tumoren bei Patienten mit Kontraindikation gegen platinhaltige Chemotherapie.Patientengut und Methode:10 Patienten mit lokal fortgeschrittenen rezidivierten HNO-Tumoren wurden retrospektiv ausgewertet. In 9 Fällen lag histologisch ein Plattenepithelkarzinom, in einem Fall ein adenoidzystisches Karzinom vor. In jedem Fall war eine Strahlentherapie Teil des initialen Behandlungskonzeptes. Die Re-Bestrahlung wurde mittels Step-and-shoot-IMRT mit einer medianen Dosis von 50,4 Gy durchgeführt. Cetuximab wurde als „Loading Dose“ (400 mg/m2) eine Woche vor Re-Bestrahlung und danach wöchentlich simultan zur Bestrahlung (250 mg/m2) verabreicht.Ergebnisse:Das mediane Gesamtüberleben nach Re-Bestrahlung war 7 Monate; das 1-Jahres-Gesamtüberleben betrug 40%. Ein Lokalrezidiv trat bei 3 Patienten auf, was zu einer 1-Jahres-Lokalkontrolle von 61% führte. Die 1-Jahres-lokoregionäre Kontrolle betrug 44%. Das 1-Jahres-Metastasen-freie Überleben war 75% (siehe Abbildungen 1–4). Eine akute hämatologische Toxizität wurde in diesem Kollektiv nicht gesehen. Schwere Akuttoxizitäten waren eine fatale arterielle Blutung und eine Flap-Nekrose. Als schwere Spättoxizität trat eine Fibrose der Pterygiodmuskulatur bzw. des Kiefergelenks sowie eine zervikale Ösophagusstenose auf (vgl. Tabellen 2 u. 3).Schlussfolgerungen:Bei rezidivierten HNO-Tumoren ist eine IMRT-Re-Bestrahlung mit 50 Gy und simultaner Cetuximab- Immuntherapie mit einer akzeptablen Toxizität durchführbar. Es sind weitere Untersuchungen nötig, um den Stellenwert dieser Therapieform zu überprüfen.

Intensity modulated radiotherapy (IMRT) in benign giant cell tumors – a single institution case series and a short review of the literature

BackgroundGiant cell tumors are rare neoplasms, representing less than 5% of all bone tumors. The vast majority of giant cell tumors occurs in extremity sites and is treated by surgery alone. However, a small percentage occurs in pelvis, spine or skull bones, where complete resection is challenging. Radiation therapy seems to be an option in these patients, despite the lack of a generally accepted dose or fractionation concept. Here we present a series of five cases treated with high dose IMRT.Patients and MethodsFrom 2000 and 2006 a total of five patients with histologically proven benign giant cell tumors have been treated with IMRT in our institution. Two patients were male, three female, and median age was 30 years (range 20 -- 60). The tumor was located in the sacral region in four and in the sphenoid sinus in one patient. All patients had measurable gross disease prior to radiotherapy with a median size of 9 cm. All patients were treated with IMRT to a median total dose of 64 Gy (range 57.6 Gy to 66 Gy) in conventional fractionation.ResultsMedian follow up was 46 months ranging from 30 to 107 months. Overall survival was 100%. One patient developed local disease progression three months after radiotherapy and needed extensive surgical salvage. The remaining four patients have been locally controlled, resulting in a local control rate of 80%. We found no substantial tumor shrinkage after radiotherapy but in two patients morphological signs of extensive tumor necrosis were present on MRI scans. Decline of pain and/or neurological symptoms were seen in all four locally controlled patients. The patient who needed surgical salvage showed markedly reduced pain but developed functional deficits of bladder, rectum and lower extremity due to surgery. No severe acute or late toxicities attributable to radiation therapy were observed so far.ConclusionIMRT is a feasible option in giant cells tumors not amendable to complete surgical removal. In our case series local control was achieved in four out of five patients with marked symptom relief in the majority of cases. No severe toxicity was observed.

Intensity modulated or fractionated stereotactic reirradiation in patients with recurrent nasopharyngeal cancer

PurposeTo report our experience with intensity-modulated or stereotactic reirradiation in patients suffering from recurrent nasopharyngeal carcinomaPatients and MethodsThe records of 17 patients with recurrent nasopharygeal carcinoma treated by intensity-modulated (n = 14) or stereotactic (n = 3) reirradiation in our institution were reviewed. Median age was 53 years and most patients (n = 14) were male. The majority of tumors showed undifferentiated histology (n = 14) and infiltration of intracranial structures (n = 12). Simultaneous systemic therapy was applied in 8 patients. Initial treatment covered the gross tumor volume with a median dose of 66 Gy (50-72 Gy) and the cervical nodal regions with a median dose of 56 Gy (50-60 Gy). Reirradiation was confined to the local relapse region with a median dose of 50.4 Gy (36-64Gy), resulting in a median cumulative dose of 112 Gy (91-134 Gy). The median time interval between initial and subsequent treatment was 52 months (6-132).ResultsThe median follow up for the entire cohort was 20 months and 31 months for survivors (10-84). Five patients (29%) developed isolated local recurrences and three patients (18%) suffered from isolated nodal recurrences. The actuarial 1- and 2-year rates of local/locoregional control were 76%/59% and 69%/52%, respectively. Six patients developed distant metastasis during the follow up period. The median actuarial overall survival for the entire cohort was 23 months, transferring into 1-, 2-, and 3-year overall survival rates of 82%, 44% and 37%. Univariate subset analyses showed significantly increased overall survival and local control for patients with less advanced rT stage, retreatment doses > 50 Gy, concurrent systemic treatment and complete response. Severe late toxicity (Grad III) attributable to reirradiation occurred in five patients (29%), particularly as hearing loss, alterations of taste/smell, cranial neuropathy, trismus and xerostomia.ConclusionReirradiation with intensity-modulated or stereotactic techniques in recurrent nasopharyngeal carcinoma is feasible and yields encouraging results in terms of local control and overall survival in patients with acceptable toxicity in patients with less advanced recurrences. However, the achievable outcome is limited in patients with involvement of intracranial structures, emphasising the need for close monitoring after primary therapy.

Total skin electron beam therapy as palliative treatment for cutaneous manifestations of advanced, therapy-refractory cutaneous lymphoma and leukemia

BackgroundTo retrospectively access the outcome and toxicity of a total skin electron beam therapy (TSEBT) in patients with cutaneous lymphoma (CL) or leukemia.Patients and methodsTreatment results of 25 patients (median age 63 years; 5 female, 20 male) with cutaneous manifestations of advanced and therapy-refractory CL (n = 21; T-cell lymphomas n = 18, B-cell lymphomas n = 3) stage IIB-IV or leukemia (n = 4; AML n = 2, CLL n = 1, PDC n = 1) treated between 1993 and 2010 were reviewed. All patients were symptomatic. The median total dose was 29Gy, applied in 29 fractions of median 1 Gy each.ResultsThe median follow-up was 10 months. Palliation was achieved in 23 patients (92%). A clinical complete response was documented in 13 (52%) and a partial response in 10 patients (40%). The median time to skin progression was 5 months (range 1–18 months) and the actuarial one-year progression-free survival 35%. The median overall survival (OS) after the initiation of TSEBT was 10 months (range 1–46 months) and the actuarial one-year OS 45%. TSEBT related acute adverse events (grade 1 or 2) were observed in all patients during the treatment period. An acute grade 3 epitheliolysis developed in eight patients (32%). Long-term adverse events as a hyperpigmentation of the skin (grade 1 or 2) were documented in 19 patients (76%), and a hypohidrosis in seven patients (28%).ConclusionFor palliation of symptomatic cutaneous manifestations of advanced cutaneous lymphoma or leukemia, total skin electron beam therapy is an efficient and well tolerated considerable treatment option.

Reirradiation with intensity-modulated radiotherapy in recurrent head and neck cancer

In this retrospective investigation we analyzed outcome and toxicity after intensity‐modulated reirradiation of recurrent head and neck cancer.

New multileaf collimator with a leaf width of 5 mm improves plan quality compared to 10 mm in step-and-shoot IMRT of HNC using integrated boost procedure

Purpose:To investigate whether a new multileaf collimator with a leaf width of 5 mm (MLC-5) over the entire field size of 40 × 40 cm2 improves plan quality compared to a leaf width of 10 mm (MLC-10) in intensity-modulated radiotherapy (IMRT) with integrated boost for head and neck cancer.Patients and Methods:A plan comparison was performed for ten patients with head and neck cancer. For each patient, seven plans were calculated: one plan with MLC-10 and nine beams, four plans with MLC-5 and nine beams (with different intensity levels and two-dimensional median filter sizes [2D-MFS]), and one seven-beam plan with MLC-5 and MLC-10, respectively. Isocenter, beam angles and planning constraints were not changed. Mean values of common plan parameters over all ten patients were estimated, and plan groups of MLC-5 and MLC-10 with nine and seven beams were compared.Results:The use of MLC-5 led to a significantly higher conformity index and an improvement of the 90% coverage of PTV1 (planning target volume) and PTV2 compared with MLC-10. This was noted in the nine- and seven-beam plans. Within the nine-beam group with MLC-5, a reduction of the segment number by up to 25% at reduced intensity levels and for increased 2D-MFS did not markedly worsen plan quality. Interestingly, a seven-beam IMRT with MLC-5 was inferior to a nine-beam IMRT with MLC-5, but superior to a nine-beam IMRT with MLC-10.Conclusion:The use of an MLC-5 has significant advantages over an MLC-10 with respect to target coverage and protection of normal tissues in step-and-shoot IMRT of head and neck cancer.Ziel:Gegenstand dieser Untersuchung war, ob bei der intensitätsmodulierten Radiotherapie (IMRT) von Kopf-Hals-Tumoren mit integriertem Boost ein neuer kommerzieller Multileafkollimator mit einer Lamellenblende von 5 mm (MLC-5) über eine Feldgröße von 40 × 40 cm2 zu einer Verbesserung der Planqualität im Vergleich zu einer Lamellenblende von 10 mm (MLC-10) führt.Patienten und Methodik:Der Planvergleich wurde an zehn Patienten mit Kopf-Hals-Tumoren durchgeführt. Für jeden Patienten wurden sieben Pläne berechnet: ein Plan mit MLC-10 und neun Feldern, vier Pläne mit MLC-5 und neun Feldern (mit verschiedenen Intensitätsleveln bzw. zweidimensionalen Medianfiltergrößen [2D-MFS]) und je ein Sieben-Felder-Plan mit MLC-5 und MLC-10. Isozentrum, Feldwinkel und Planungsbeschränkungen blieben unverändert. Es wurden Mittelwerte der üblichen Planparameter von allen zehn Patienten berechnet und die Plangruppen mit MLC-5 und MLC-10 bzw. neun und sieben Feldern miteinander verglichen.Ergebnisse:Der Einsatz eines MLC-5 führt im Vergleich zu einem MLC-10 zu einer signifikanten Verbesserung des Konformitätsindex und zu einer Erhöhung von V90 des PTV1 (Planungszielvolumen) und PTV2 (Tabellen 1–4, Abbildung 3). Dies konnte für Neun- und Sieben-Felder-Pläne gezeigt werden. Innerhalb der Neun-Felder-Plangruppen mit MLC-5 führte eine Verringerung der Segmentanzahl um 25% durch Reduktion der Intensitätslevel und/oder des 2D-MFS nicht zu einer Verschlechterung der Planqualität (Abbildung 2). Eine Sieben-Felder-IMRT mit MLC-5 war einer Neun-Felder-IMRT mit MLC-5 unterlegen, aber besser als eine Neun-Felder-IMRT mit MLC-10.Schlussfolgerung:Die Verwendung eines MLC-5 weist gegenüber einem MLC-10 signifikante Vorteile bezüglich der Zielvolumenabdeckung und der Normalgewebsschonung bei der „step-and-shoot“-IMRT von Kopf-Hals-Tumoren mit integrierter Boostapplikation auf.

Intensity modulated radiotherapy (IMRT) combined with concurrent but not adjuvant chemotherapy in primary nasopharyngeal cancer – a retrospective single center analysis

BackgroundWe report our experience in 49 consecutive patients with nasopharyngeal carcinoma who were treated by Intensity-modulated radiation therapy (IMRT) combined with simultaneous but not adjuvant chemotherapy (CHT).MethodsThe medical records of 49 patients with histologically proven primary nasopharygeal carcinoma treated with IMRT and concurrent platin-based CHT (predominantly cisplatin weekly) were retrospectively reviewed. The majority of patients showed advanced clinical stages (stage III/IV:72%) with undifferentiated histology (82%). IMRT was performed in step-and-shoot technique using an integrated boost concept in 84%. In this concept, the boost volume covered the primary tumor and involved nodes with doses of 66–70.4 Gy (single dose 2.2 Gy). Uninvolved regional nodal areas were covered with doses of 54–59.4 Gy (median single dose 1.8 Gy). At least one parotid gland was spared. None of the patients received adjuvant CHT.ResultsThe median follow-up for the entire cohort was 48 months. Radiation therapy was completed without interruption in all patients and 76% of the patients received at least 80% of the scheduled CHT. Four local recurrences have been observed, transferring into 1-, 3-, and 5-year Local Control (LC) rates of 98%, 90% and 90%. One patient developed an isolated regional nodal recurrence, resulting in 1-, 3-, and 5-year Regional Control (RC) rates of 98%. All locoregional failures were located inside the radiation fields. Distant metastases were found in six patients, transferring into 1-, 3, and 5-year Distant Control (DC) rates of 92%, 86% and 86%. Progression free survival (PFS) rates after 1, 3 and 5 years were 86%, 70% and 69% and 1-, 3- and 5-year Overall Survival (OS) rates were 96%, 82% and 79%. Acute toxicity ≥ grade III mainly consisted of dysphagia (32%), leukopenia (24%), stomatitis (16%), infection (8%) and nausea (8%). Severe late toxicity (grade III) was documented in 18% of the patients, mainly as xerostomia (10%).ConclusionConcurrent chemoradiation without the addition of adjuvant chemotherapy cycles using IMRT with an integrated boost concept yielded good disease control and overall survival in patients suffering from primary nasopharyngeal cancer with acceptable acute side effects and limited rates of late toxicity.

A specific inhibitor of protein kinase CK2 delays gamma-H2Ax foci removal and reduces clonogenic survival of irradiated mammalian cells.

BackgroundThe protein kinase CK2 sustains multiple pro-survival functions in cellular DNA damage response and its level is tightly regulated in normal cells but elevated in cancers. Because CK2 is thus considered as potential therapeutic target, DNA double-strand break (DSB) formation and rejoining, apoptosis induction and clonogenic survival was assessed in irradiated mammalian cells upon chemical inhibition of CK2.MethodsMRC5 human fibroblasts and WIDR human colon carcinoma cells were incubated with highly specific CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB), or mock-treated, 2 hours prior to irradiation. DSB was measured by pulsed-field electrophoresis (PFGE) as well as gamma-H2AX foci formation and removal. Apoptosis induction was tested by DAPI staining and sub-G1 flow cytometry, survival was quantified by clonogenic assay.ResultsTBB treatment did not affect initial DNA fragmention (PFGE; up to 80 Gy) or foci formation (1 Gy). While DNA fragment rejoining (PFGE) was not inhibited by the drug, TBB clearly delayed gamma-H2AX foci disappearence during postirradiation incubation. No apoptosis induction could be detected for up to 38 hours for both cell lines and exposure conditions (monotherapies or combination), but TBB treatment at this moderately toxic concentration of 20 μM (about 40% survival) enhanced radiation-induced cell killing in the clonogenic assay.ConclusionsThe data imply a role of CK2 in gamma-H2AX dephosporylation, most likely through its known ability to stimulate PP2A phosphatase, rather than DSB rejoining. The slight but definite clonogenic radiosensitization by TBB does apparently not result from interference with an apoptosis suppression function of CK2 in these cells but could reflect inhibitor-induced uncoupling of DNA damage response decay from break ligation.

Palliative Radiotherapy of Retrobulbar Orbit Metastases due to Breast Cancer

Background: In breast cancer, the occurrence of retrobulbar metastases of the orbit is rare compared to intraocular metastases. The clinical symptoms are quite different. Impairment of vision, exophthalmus, double vision, vertigo, and pain reduce patients’ quality of life. Patients and Methods: The benefit of palliative irradiation of the orbit was researched retrospectively in 7 patients. This report also presents the first case in the literature of a breast cancer patient with bi-orbital enophthalmus caused by bilateral retrobulbar metastases that were successfully treated with radiotherapy. Irradiation was performed by photon or electron beams (20–50 Gy). Clinical restaging was done at the end of radiotherapy and 6 weeks thereafter. Results: After irradiation, 6 out of 7 patients showed a distinct clinical response with good palliation and no major side effects. Exophthalmus, pain, and vertigo were significantly reduced in all cases. Double vision disappeared in 3 out of 4 patients, eye muscle paralysis in 5 out of 6 patients. The median overall survival after irradiation of the orbit was 7.3 months. Conclusion: Palliative radiotherapy of retrobulbar metastases of breast cancer is very effective in reducing acute clinical symptoms and increasing quality of life. Nonetheless, patients have a poor prognosis.

Treatment of squamous cell carcinoma of the mobile tongue or tongue margins: An interdisciplinary challenge

Abstract Background. Standard treatment is surgery with stage dependent postoperative radio(chemo)therapy, however, for organ preservation preoperative radio(chemo)therapy is used as an individual approach. The present analysis was performed to access outcome and toxicity of radiotherapeutical treatment of squamous cell carcinoma of the tongue. Patients and methods. Sixty-six patients (median age 55 years) with cancer of the mobile tongue (n30) or tongue margins (n36) treated between 1982 and 2006 were retrospectively analyzed. Treatment consisted of definitive- (n13, median dose 66 Gy), adjuvant- (n31, median dose 60 Gy) or neoadjuvant radiotherapy (n22, median dose 40 Gy) and chemotherapy (n34) or immunotherapy (n1). Results. After a median follow-up of 29 months the three- and five-year overall survival (OS) rates were 59% and 46%, respectively. The median OS was 54 months. Forty-two patients achieved complete remission whereas 14 patients showed partial remission. The one- and two-year loco-regional progression-free survival (LRPFS) rates were 76% and 58%, respectively. The median LRPFS time was 36 months. In χ2-test, T-stage showed a trend towards impact on local recurrence (Pearson, p0.082). In multivariate analysis, alcohol consumption (p0.003) and gender (p0.031) were prognostic. Grade III/IV acute toxicity was seen in 52% of patients. None of the locally controlled patients reported grade IV or higher late toxicity. Conclusion. No statistically significant differences between treatment modalities were found, but one should keep in mind that organ preservation plays a major role for quality of life. None of the locally controlled patients reported grade IV or higher late toxicity. However, tumor recurrence is common, especially in advanced tumor stage. Interdisciplinary concepts, further increasing the chance of tumor control are warranted.