Leo Pfreundner

Radiotherapy in adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare malignancy, and patients with ACC have a poor prognosis. Even after radical surgery, up to 85% of patients develop recurrent disease. Systemic treatment options still have limited efficacy. Because the role of radiotherapy is not defined well and because ACC often is considered radioresistant, the authors reviewed the available data on radiotherapy for ACC. Original articles and reviews were identified using a PubMed search strategy that included the period up to July 2008. Ten articles were identified that covered radiotherapy in a total of 129 patients with ACC (64 patients received postoperative irradiation, and 65 patients received palliative therapy for advanced disease). In addition, 26 patients were identified in the German ACC Registry who received palliative radiotherapy. Furthermore, patterns of failure after adjuvant radiotherapy were investigated, and the authors provided recommendations for patient selection, treatment planning, and treatment protocols. In an adjuvant setting, postoperative radiotherapy was able to prevent local recurrence in the majority of patients. In those with advanced disease, a response to radiotherapy was observed in 57% of patients who received palliative radiotherapy. Therefore, the authors concluded that radiotherapy may play an important role in the care of patients with ACC. Until better evidence is available, the authors recommended the following approach: Adjuvant radiotherapy to the tumor bed should be considered in patients at high risk for local recurrence (eg, incomplete/R1 resection); a total dose of >40 grays (Gy) with single fractions of 1.8 Gy to 2 Gy should be administered (including a boost volume to reach from 50 Gy to 60 Gy in individual patients); and radiotherapy in a palliative setting may be used for symptomatic metastases to bone, brain, or vena cava obstruction. With state‐of‐the‐art technology, acute and long‐term toxicities mostly were mild to moderate. However, the authors concluded that prospective investigations would be required to fully define the therapeutic potential of this important treatment option. Cancer 2009.

Carcinoma of the external auditory canal and middle ear

PURPOSE To evaluate therapeutic modalities used at our institutions regarding local control, disease-free survival and actuarial survival in carcinoma of the external auditory canal and middle ear, in an attempt to provide guidelines for therapy. METHODS AND MATERIALS A series of 27 patients with carcinoma of the external auditory canal and middle ear treated between 1978 and 1997 in our institutions were analyzed with particular reference to tumor size and its relation to surrounding tissues, patterns of neck node involvement, surgical procedures, and radiation techniques employed. Clinical endpoints were freedom from local failure, overall survival, and disease-free survival. The median follow-up was 2.7 years (range 0.1-17.9 years). RESULTS Treatment by surgery and radiotherapy resulted in an overall 5-year survival rate of 61%. According to the Pittsburgh classification, the actuarial 5-year survival rate for early disease (T1 and T2 tumors) was 86%, for T3 tumors 50%, and T4 stages 41%. Patients with tumors limited to the external auditory canal had a 5-year survival rate of 100%, patients with tumor invasion of the temporal bone 63%, and patients with tumor infiltration beyond the temporal bone 38%. The rate of freedom from local recurrence was 50% at 5 years. Unresectability by dural and cerebral infiltration, and treatment factors such as complete resection or resection with tumor beyond surgical margins are of prognostic relevance. All patients with dural invasion died within 2.2 years. The actuarial 5-year survival rate of patients with complete tumor resection was 100%, but 66% in patients with tumor beyond surgical margins. 192Iridium high-dose-rate (HDR) afterloading brachytherapy based on three-dimensional computed tomography (3D CT)-treatment planning was an effective tool in management of local recurrences following surgery and a full course of external beam radiotherapy. CONCLUSION Surgical resection followed by radiotherapy adapted to stage of disease and grade of resection is the preferred treatment of cancer of the external auditory canal and middle ear.

Hyperfractionated accelerated radiotherapy in combination with weekly cisplatin for locally advanced head and neck cancer

The purpose of this study was to determine the feasibility and efficacy of hyperfractionated accelerated radiotherapy (HFRCB) combined with simultaneous chemotherapy with weekly cisplatin (CDDP) in locally advanced inoperable head and neck cancer.

The influence of the radicality of resection and dose of postoperative radiation therapy on local control and survival in carcinomas of the upper aerodigestive tract

PURPOSE To evaluate dose concepts in postoperative irradiation of carcinomas of the upper aerodigestive tract according to the radicality of resection. PATIENTS AND METHODS In a retrospective analysis, the charts of 257 patients with histologically-proven carcinoma of the upper aerodigestive tract (40 T1, 80 T2, 53 T3, 84 T4 tumors, with nodal involvement in 181 cases) were reviewed according to the radicality of resection and dose of irradiation administered. Sixty-four patients had tumor-free resection margins (> 3 mm), 66 patients had close resection margins (< 3 mm), and 101 patients had R1 resections, and 26 patients had R2 resections. A median dose of 56 Gy was applied to the primary tumor bed and the cervical lymphatics (2 Gy/fraction, 5 fractions/week). In cases of R1 or R2 resection, or of close margins (< 3 mm), the tumor bed or, respectively, tumor residuals were boosted with doses up to a median of 66 Gy. Locoregional tumor control and survival was investigated by uni- and multivariate analyses according to T-, N-stage, grade of resection, total dose of radiation, and presence or absence of extracapsular tumor spread and lymphangiosis carcinomatosa. RESULTS An overall 3- and 5-year survival rate of 60% and 45%, respectively, was achieved. Rates for freedom from locoregional recurrence were 77% and 72% at 3 and 5 years, respectively. The survival rates according to the grade of resection at 5 years were 67% for patients resected with tumor-free margins, 59% for patients resected with close margins, 26% for patients with R1 resection, and 27% for patients with R2 resection. Within a median follow-up period of 4.7 years for living patients, a total of 67 recurrences (26%) were observed (in 9% of patients resected with tumor-free margins, in 27% with close margins, in 37% of R1 resected, and in 19% of R2 resected patients). Freedom from locoregional recurrence at 3 years was achieved in 100% of the patients resected with tumor-free margins, in 92% of patients resected with close surgical margins, in 87% of R1 and 69% of R2 resected patients. In multivariate Cox-regression analysis, the variables grade of resection (p = 0.00031) and total dose of irradiation (p = 0.0046) were found as factors influencing locoregional control. Variables influencing survival according to multivariate analysis are T-stage (p = 0.0057), N-stage (p = 0.024), grade of resection (p = 0.000015), total dose of irradiation (p < 0. 000000). Extracapsular tumor spread and lymphangiosis carcinomatosa are factors of borderline significance (p = 0.055, p = 0.066). CONCLUSION In postoperative radiotherapy of head and neck carcinomas, doses adapted to the risk of locoregional recurrent disease should be applied. Patients with R1 and R2 resections should be treated with doses of more than 68 Gy (2 Gy/fraction, 5 fractions/week) (with close margins [< 3 mm] more than 66 Gy) to achieve an improvement in locoregional control and survival.

Induction chemotherapy with paclitaxel and cisplatin and CT-based 3D radiotherapy in patients with advanced laryngeal and hypopharyngeal carcinomas--a possibility for organ preservation.

BACKGROUND To evaluate the effect of paclitaxel/cisplatin induction chemotherapy (ICHT) and CT-based radiotherapy (RT) on larynx preservation, tumor control, and survival in patients with larynx/hypopharynx carcinoma eligible for total laryngectomy (TL) or TL plus partial pharyngectomy (TLPP). PATIENTS AND METHODS Fifty patients eligible for TL or TLPP were enrolled onto a prospective study and treated with ICHT (200 mg/m(2) paclitaxel, 100 mg/m(2) cisplatin; day 1, 22). In patients with complete or partial tumor response RT (69.9 Gy in 5.5 weeks at the gross tumor, 50.4 Gy in the lymphatic drainage; single dose: 1.8 Gy, concomitant boost: 1.5 Gy) was applied. Non-responders had TL/TLPP and RT with total doses adapted to the radicality of tumor resection (56-70 Gy). RESULTS The response rate to ICHT was 88% (10% complete, 78% partial response). At a median follow-up period of 25 months the larynx preservation rate was 84%. The 2-year local-regional control rate was 91% and the 2-year overall survival rate was 72.3%. The 3-year estimate to survive with functional larynx is 60%. CONCLUSION In a large portion of patients eligible for TL or TLPP the larynx was preserved by paclitaxel/cisplatin ICHT and 3D RT.

Radiation techniques for head and neck tumors.

PURPOSE A technique that combines some advantages of conforming techniques for advanced oro- and hypopharyngeal carcinomas is proposed. The aim is to increase the dose homogeneity in the target volume relative to lateral opposed fields. METHODS AND MATERIALS This publication compares conforming radiation techniques based on standard equipment, standard linear accelerator setup and commercially available planning software with lateral opposed fields. More advanced conformal techniques reported in the literature are taken into account in a semi-quantitative manner. Our standard method uses an arc rotation, sparing the spinal cord. In contrast to earlier methods of this type, the resulting dose deficit in the vicinity of the spine is compensated by static lateral wedged fields. Dose distributions for 25 consecutive patients were planned. RESULTS The conforming techniques were found to produce more homogeneous dose distributions than lateral opposed fields. In the planning target volume (PTV) (mean: 940 cm(3)) a standard deviation of dose of 4.6% was achieved. Ninety-five percent of the PTV were enclosed by the 90% isodose. The maximal spinal cord dose was limited to 45 Gy. The dose distributions of these techniques could compete with literature data on advanced techniques (the published dose-volume histogram (DVHs) of PTVs were evaluated). At the linear accelerator time for realization took 14 min on average. The planning time is 1-4 h (mean: less than 2 h). CONCLUSION A rotational technique applicable with standard equipment is presented. Dose coverage of target volumes is improved, while the spinal cord is spared.

Systematics in lymphatic tumor spread of carcinomas of the upper aerodigestive tract : a clinical study based on embryologic data

Background: The aim of this study was to assess the incidence and pattern of cervical lymph node (LN) metastases in carcinomas of the upper aerodigestive tract in relation to primary tumor (PT) invasion of the equivalents of pharyngeal arches (PhA) and occipital and cervical somites (OCS) in adults. Methods: The pretherapeutic computed tomography scans and clinical findings in 729 patients with histologically proven carcinoma of the upper aerodigestive tract (112 nasopharyngeal, 289 oropharyngeal, 252 laryngo-hypopharyngeal, and 76 oral cavity carcinomas, with LN involvement in 70% of the total) were analyzed in relation to PT invasion of equivalents of PhA and OCS. Tumors were recorded according to the infiltration of these equivalents. The metastatic involvement of the different cervical LN groups was analyzed and correlated to the pattern of PT invasion of equivalents of PhA and OCS by the chi-square test. Results: The findings show that the pattern of cervical LN involvement depends on the location and extension of the PT and its invasion of equivalents of the PhA and OCS. Jugular LN metastases were found in tumors invading the equivalents of PhA 2–6. Submandibular LN metastases were evident in tumors invading tissues arising from the first PhA and the tongue. Retropharyngeal, spinal accessory and transversa colli LN metastases were found in tumors invading tissues arising from OCS. The frequency of LN metastases in the different LN chains decreased in the cranio-caudal direction. Each neck hemisphere showed separate lymphatic drainage. Conclusions: Analysis of PT extension in relation to PhA and OCS equivalents allows patterns of LN involvement to be predicted.

Micronucleus formation kinetics in buccal mucosa cells of head and neck cancer patients undergoing radiotherapy.

In head and neck cancer, radiotherapy is one of the main treatment modalities besides surgery and chemotherapy either in a primary or an adjuvant setting. Radiation kills tumor cells by damaging the DNA within these cells. One of the methods to assess the degree of genomic damage is the micronucleus (MN) test. The effect of radiation therapy on the MN frequency in buccal mucosa cells has only been investigated in small studies looking at single time points or including a limited number of patients. In the present study, normal tissue buccal mucosa cells from 17 patients were analyzed for genomic damage at four different time points during radiation therapy. A clear increase was observed for every time point. Additionally, buccal mucosa cells of a cohort of 16 patients were analyzed after the end of the therapy and compared to samples from 25 patients sampled before the therapy. 10 healthy controls were included, of which 5 were sampled once, and 5 were sampled four times similar to the patients. Also, the influence of additional chemotherapy was investigated. No difference was observed between radiation-only patients and patients receiving additional chemotherapy. Age, gender, and tumor stage did not have an influence on the MN formation kinetics.

3D-CT-geplante interstitielle HDR-Brachytherapie + perkutane Bestrahlung und Chemotherapie bei inoperablen Pankreaskarzinomen

PURPOSE Clinical experiences in interstitial 192-iridium HDR brachytherapy for the treatment of unresectable pancreatic carcinoma are presented. Brachytherapy has been used as boost irradiation in a multimodality treatment concept together with external radiotherapy and simultaneous chemotherapy. Practicability during clinical routine, tolerability and toxicity of treatment are investigated. PATIENTS AND METHODS Nineteen patients (9 female, 10 male, median age 67 years) with unresectable carcinoma of the pancreas have been treated with interstitial brachytherapy. Distribution according to UICC stages showed 4, 10 and 5 patients in stage II to IV respectively. In all cases afterloading technique with 192-iridium in HDR-modus was used. A total dose of 10 to 34 Gy to the reference isodose was delivered (single dose 1.88 to 5 Gy, median 2.5 Gy). Brachytherapy was followed by external radiotherapy, delivering an additional dose of 40 to 58 Gy. Nine patients received simultaneous chemotherapy (5-fluorouracil, leucovorin). Treatment planning was performed based on CT scans, allowing spatial correlation of isodose curves to the patients anatomy. RESULTS Median survival time was 6 months. A trend of lower survival rates with advanced stage of disease (median survival stage IV 4 months, stage II and III 6.5 months) was seen. Local control rate was 70%. Brachytherapy treatment was well tolerated, severe acute side effects were not observed. One patient developed pancreatic fistulae 4 months and 1 patient a gastric ulcer 7 months after treatment. Pain release was achieved in all patients. CONCLUSIONS 192-iridium HDR-brachytherapy is an effective tool in the treatment of unresectable pancreatic carcinoma with a high rate of local control and a low rate of side effects and is comparable IORT or seed implantation.ZusammenfassungZielUntersuchung der Praktikabilität, Verträglichkeit und Nebenwirkungen der interstitiellen 192-Iridium-HDR-Brachytherapie im Afterloadingverfahren in der Behandlung des nichtresektablen Pankreaskarzinoms. Die Brachytherapie wurde dabei als Boostbehandlung im Rahmen eines multimodalen therapiekonzepts, bestehend aus interstiteller Brachytherapie, perkutaner Radiatio und simultaner Chemotherapie, eingesetzt.Patienten und Methoden19 Patienten (neun Frauen, zehn Männer) mit einem inoperablen Adenokarzinom des Pankreas (UICC-Stadium IV n=5, Stadium III n=10, Stadium II n=4) im Alter von median 67 Jahren wurden mit einer interstitiellen Brachytherapie mit 192-Iridium HDR im Afterloadingverfahren behandelt. Die auf die Referenzisodose eingestrahlten Dosen lagen zwischen 10 und 34 Gy, bei Einzeldosen von 1,88 bis 5 Gy (median 2,0 Gy). Der interstitiellen Therapie schloß sich eine perkutane Radiatio mit Gesamtdosen zwischen 40 und 58 Gy an. Bei neun Patienten wurde zusätzlich eine Chemotherapie mit 5-Fluorouracil und Leucovorin appliziert. Für die interstitielle Brachytherapie wurde ein CT-gestütztes Planungsverfahren angewandt, das eine räumliche Zuordnung der Isodosenverteilung zur Patientenanatomie gestattet.ErgebnisIm Patientenkollektiv wurde eine mediane Überlebenszeit von sechs Monaten beobachtet, wobei sich ein Trend zur Abhängigkeit der Überlebenszeit vom Stadium der Tumorerkrankung zeigt (mediane Überlebenszeit Stadium IV vier Monate, Stadium II und III 6,5 Monate). Die lokale Tumorkontrollrate lag bei etwa 70%. Die Therapie zeichnete sich durch eine gute Verträglichkeit aus. Schwerwiegende akute Nebenwirkungen wurden nicht beobachtet. Eine Pankreasfistelung wurde vier Monate und ein unkompliziertes Magenulkus sieben Monate nach Therapiebeginn beobachtet. Bei allen Patienten konnte eine rasche und anhaltende Schmerzlinderung erreicht werden.SchlußfolgerungDie 3D-CT-geplante interstitielle HDR-Brachytherapie zeichnet sich beim nichtresektablen Pankreaskarzinom durch die geringe Nebenwirkungsrate im Vergleich zu konkurrierenden Verfahren wie der IORT und der interstitiellen Seedimplantation aus. Trotz der hohen lokalen Kontrollrate kann durch die frühzeitig einsetzende Fernmetastasierung keine Steigerung der medianen Überlebenszeit im Vergleich mit konkurrierenden Therapieverfahren erreicht werden.AbstractPurposeClinical experiences in interstitial 192-iridium HDR brachytherapy for the treatment of unresectable pancreatic carcinoma are presented. Brachytherapy has been used as boost irradiation in a multimodality treatment concept together with external radiotherapy and simultaneous chemotherapy. Practicability during clinical routine, tolerability and toxicity of treatment are investigated.Patients and MethodsNineteen patients (9 female, 10 male, median age 67 years) with unresectable carcinoma of the pancreas have been treated with interstitial brachytherapy. Distribution according to UICC stages showed 4, 10 and 5 patients in stage II to IV respectively. In all cases afterloading technique with 192-iridium in HDR-modus was used. A total dose of 10 to 34 Gy to the reference isodose was delivered (single dose 1.88 to 5 Gy, median 2.5 Gy). Brachytherapy was followed by external radiotherapy, delivering an additional dose of 40 to 58 Gy. Nine patients received simulatenous chemotherapy (5-fluorouracil, leucovorin). Treatment planning was performed based on CT scans, allowing spatial correlation of isodose curves to the patient’s anatomy.ResultsMedian survival time was 6 months. A trend of lower survival rates with advanced stage of disease (median survival stage IV 4 months, stage II and III 6.5 months) was seen. Local control rate was 70%. Brachytherapy treatment was well tolerated, severe acute side effects were not observed. One patient developed pancreatic fistulae 4 months and 1 patient a gastric ulcer 7 months after treatment. Pain release was achieved in all patients.Conclusions192-iridium HDR-brachytherapy is an effective tool in the treatment of unresectable pancreatic carcinoma with a high rate of local control and a low rate of side effects and is comparable IORT or seed implantation.

Cytotoxic and Genotoxic Effects of Paclitaxel (Taxol®) and Radiation in a Squamous Cell Carcinoma Cell Line of the Larynx

Paclitaxel (Taxol) is an antimicrotubular agent which blocks the cells in the G2/M phase of the cell cycle. Because of this mechanism it is presumed that this drug could function as a radiation sensitizer. The cytotoxic and genotoxic effects of paclitaxel and a combination of paclitaxel and radiation were studied in the human laryngeal carcinoma cell line HLac 79. The growth of the cells was significantly reduced at concentrations of paclitaxel as low as 10 nM. Flow cytometry data showed a G2/M block after exposure to paclitaxel. Radiation at 12 and 24 h after drug treatment exerted an additive but no radiation sensitizing effect. As genotoxic effect paclitaxel induced multinucleated cells, possibly in a synergistic manner, at low concentrations (10 nM) and radiation doses up to 3 Gy.