Karl T. Beer

Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial

BACKGROUND Anaemia is associated with poor cancer control, particularly in patients undergoing radiotherapy. We investigated whether anaemia correction with epoetin beta could improve outcome of curative radiotherapy among patients with head and neck cancer. METHODS We did a multicentre, double-blind, randomised, placebo-controlled trial in 351 patients (haemoglobin <120 g/L in women or <130 g/L in men) with carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received curative radiotherapy at 60 Gy for completely (R0) and histologically incomplete (R1) resected disease, or 70 Gy for macroscopically incompletely resected (R2) advanced disease (T3, T4, or nodal involvement) or for primary definitive treatment. All patients were assigned to subcutaneous placebo (n=171) or epoetin beta 300 IU/kg (n=180) three times weekly, from 10-14 days before and continuing throughout radiotherapy. The primary endpoint was locoregional progression-free survival. We assessed also time to locoregional progression and survival. Analysis was by intention to treat. FINDINGS 148 (82%) patients given epoetin beta achieved haemoglobin concentrations higher than 140 g/L (women) or 150 g/L (men) compared with 26 (15%) given placebo. However, locoregional progression-free survival was poorer with epoetin beta than with placebo (adjusted relative risk 1.62 [95% CI 1.22-2.14]; p=0.0008). For locoregional progression the relative risk was 1.69 (1.16-2.47, p=0.007) and for survival was 1.39 (1.05-1.84, p=0.02). INTERPRETATION Epoetin beta corrects anaemia but does not improve cancer control or survival. Disease control might even be impaired. Patients receiving curative cancer treatment and given erythropoietin should be studied in carefully controlled trials.

Intratumoral microvessel density predicts local treatment failure of radically irradiated squamous cell cancer of the oropharynx

PURPOSE To determine the predictive value of intratumoral microvessel density (IMD), and of the expression of p53, vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) for the radiocurability of patients with squamous cell cancer of the oropharynx. MATERIALS AND METHODS 139 patients with squamous cell cancer of the oropharynx were radically irradiated (median dose, 74 Gy) between 1991 and 1997. Biopsies from 100 patients were processed for immunohistochemistry. IMD was determined in hot spot areas of tissue stained with anti-CD31 at a magnification of x200. Staining for p53 was considered positive if more than 10% of the cell nuclei overexpressed the protein. Immunostaining of VEGF and TSP-1 was assessed semiquantitatively. RESULTS Increasing IMD (range, 54-282) was strongly correlated with incomplete remission of both the primary tumors (p = 0.01) and lymph node metastases (p = 0.02). Moreover, multivariate Cox regression analysis revealed local failure-free survival to decline with increasing IMD (IMD continuous: risk ratio = 1.01 per increase of 1 microvessel, p = 0. 0001; IMD categorical: </= 80: baseline, 81-110: risk ratio = 2.71, 111-130: risk ratio = 4.55, > 130: risk ratio = 13.01). Neither the expression of p53, nor that of VEGF or TSP-1 was associated with the treatment outcome or IMD, but VEGF and TSP-1 expression were positively correlated (p = 0.02). CONCLUSION IMD represents a powerful and independent predictive factor for local treatment failure in radically irradiated patients with squamous cell cancer of the oropharynx.

The essential role of radiotherapy in the treatment of Merkel cell carcinoma: A study from the rare cancer network

PURPOSE To evaluate the role of postoperative radiotherapy (RT) in Merkel cell carcinoma (MCC). METHODS AND MATERIALS A retrospective multicenter study was performed in 180 patients with MCC treated between February 1988 and September 2009. Patients who had had surgery alone were compared with patients who received surgery and postoperative RT or radical RT. Local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were assessed together with disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. RESULTS Seventy-nine patients were male and 101 patients were female, and the median age was 73 years old (range, 38-93 years). The majority of patients had localized disease (n = 146), and the remaining patients had regional lymph node metastasis (n = 34). Forty-nine patients underwent surgery for the primary tumor without postoperative RT to the primary site; the other 131 patients received surgery for the primary tumor, followed by postoperative RT (n = 118) or a biopsy of the primary tumor followed by radical RT (n = 13). Median follow-up was 5 years (range, 0.2-16.5 years). Patients in the RT group had improved LRFS (93% vs. 64%; p < 0.001), RRFS (76% vs. 27%; p < 0.001), DMFS (70% vs. 42%; p = 0.01), DFS (59% vs. 4%; p < 0.001), and CSS (65% vs. 49%; p = 0.03) rates compared to patients who underwent surgery for the primary tumor alone; LRFS, RRFS, DMFS, and DFS rates remained significant with multivariable Cox regression analysis. However OS was not significantly improved by postoperative RT (56% vs. 46%; p = 0.2). CONCLUSIONS After multivariable analysis, postoperative RT was associated with improved outcome and seems to be an important component in the multimodality treatment of MCC.

Prevalence and clinical impact of Met Y1253D-activating point mutation in radiotherapy-treated squamous cell cancer of the oropharynx

Aberrant signalling through the hepatocyte growth factor/scatter factor receptor Met has been implicated in various aspects of the development of human cancer including the promotion of tumour invasion, angiogenesis and metastasis. Moreover, experimental data indicate that activation of the Met receptor may be involved in cellular resistance towards antineoplastic treatments such as chemotherapy and ionizing radiation. We determined the prevalence and clinical impact of the Met-activating mutation Y1253D in patients with squamous cell cancer of the oropharynx treated by radical radiotherapy. To screen archival tissue for the presence of a low-abundance point mutation, we developed a sensitive screening method using real-time polymerase chain reaction along with peptide nucleic acid-based DNA clamping and melting curve analysis. By this approach, Met Y1253D was detected in tumours of 15 out of 138 patients (10.9%). Both univariate and multivariate survival analysis revealed Met Y1253D to be significantly associated with impaired local tumour control. Our results provide evidence that the Met-activating mutation Y1253D is present in a notable subset of patients with oropharyngeal cancer and indicate that it may interfere with radioresponsiveness of these tumours, supporting the notion of aberrant Met signalling as a potential target for radiosensitization.

MRI of Merkel Cell Carcinoma: Histologic Correlation and Review of the Literature

OBJECTIVE The objective of this study was to determine the MRI characteristics of Merkel cell carcinoma, with an emphasis on histologic correlation. MATERIALS AND METHODS The demographic information about 15 patients from our institution and their MRI examinations were retrospectively reviewed by three musculoskeletal radiologists by consensus for lesion location and intrinsic characteristics. The study group was composed of three women and 12 men who ranged in age from 48 to 87 years, with a mean age of 75 years. Histology results of resected specimens were reviewed in all cases and were correlated with imaging. RESULTS MRI showed skin thickening, subcutaneous reticular stranding (n = 9, 60%); multiple anatomically aligned subcutaneous soft-tissue masses, representing lymphatic tumor nodules (n = 5, 33%); lymph node enlargement with fine, compressed, retained fatty tissue (n = 5, 33%); nodal necrosis (n = 1); and perifascial and intramuscular metastases (n = 2). Histology confirmed the lymphatic nature of the soft-tissue Merkel cell tumors. CONCLUSION Patients with Merkel cell tumors may present at imaging with subcutaneous lymphatic reticular stranding, multiple subcutaneous masses, and lymph node metastases. Often there is massive lymph node enlargement with fine, compressed, retained fatty tissue.

No Predictive Value of the Micronucleus Assay for Patients with Severe Acute Reaction of Normal Tissue After Radiotherapy

In approximately 5% of cancer patients undergoing radiotherapy, this treatment has to be interrupted because of an acute reaction of normal tissues. To test the possibility of predicting this type of reaction, the micronucleus assay was used to determine radiosensitivities of peripheral blood lymphocytes of 15 patients with severe acute reaction of normal tissue, 15 patients without this reaction and 15 healthy donors. Whole-blood cultures were irradiated with X-rays (4 Gy, 1.08 Gy/min) and treated with cytochalasin B. The micronuclei scores observed in irradiated cells were corrected for the scores in unirradiated cells. Intra-individual and interindividual variations in micronuclei scores were analysed in samples from healthy donors, and highly significant interindividual differences were found (P < 0.001). Scores of cells not irradiated in vitro were higher for cancer patients before radiotherapy than for healthy donors (P < 0.001), and those for cancer patients after radiotherapy were higher than for patients before radiotherapy (P < 0.001). Average micronuclei scores induced by in vitro irradiation were significantly higher in samples from cancer patients compared with those from healthy donors (P < 0.01). Moreover, all subgroups of cancer patients included individuals with very high levels of micronuclei after in vitro irradiation. There was, however, no relationship between the micronuclei scores and the occurrence of severe acute reactions in normal tissues.

Expression of transforming growth factor-α, epidermal growth factor receptor and platelet-derived growth factors A and B in oropharyngeal cancers treated by curative radiation therapy

BACKGROUND AND PURPOSE Epidermal growth factor receptor (EGFR) has been implicated in cellular responses to ionizing radiation and represents a major target for current radiosensitizing strategies. We wished to ascertain whether a correlation existed between the expression of EGFR, transforming growth factor-alpha (TGFalpha) and platelet-derived growth factors A and B (PDGF-A and PDGF-B) and treatment outcome in a group of patients with oropharyngeal cancer who had undergone curative radiation therapy. We also assessed the relationship existing between each of the aforementioned proteins and intratumoral microvessel densities (IMD) which have been previously reported (Int J Radiat Oncol Biol Phys 2000;48:17-25. MATERIALS AND METHODS Pretherapeutic tumor biopsies from 95 patients were immunohistochemically stained and their immunoreactivities evaluated semi-quantitatively. The statistical analyses included Cox regression for calculating risk ratios of survival endpoints and logistic regression for determining odds ratios for the development of distant metastasis. RESULTS Local tumor control as well as disease-free and overall survival were independent of protein expression levels, whereas combined TGFalpha and EGFR immunoreactivities were closely related to IMD (P = 0.003). The expression levels of these two proteins were also correlated to each other (P = 0.015). Expression of PDGF-B occurred in 54% of cases and was associated with an increase in the risk of developing distant metastasis (P = 0.011). CONCLUSIONS Tumoral levels of TGFalpha, EGFR and PDGF-A/B are not predictive of radioresponsiveness in oropharyngeal cancers. The association between IMD and immunoreactivity for TGFalpha and EGFR indicates the involvement of these proteins in the promotion of angiogenesis in these tumors. PDGF-B should be further evaluated as a prognostic marker for squamous cell cancer of the head and neck.

Sparing of contralateral major salivary glands has a significant effect on oral health in patients treated with radical radiotherapy of head and neck tumors.

Background: Has a conscious exclusion of the contralateral major salivary glands (parotid, submandibular, and sublingual glands) a significant impact on the milieu of the oral cavity (saliva flow, pH, buffer capacity, and colonisation with Streptococcus mutans) in patients with ENT tumors receiving radical radiotherapy? Patients and Methods: 20 consecutive consentient patients with ENT tumors were evaluated once before, weekly during, and 6 weeks after the end of treatment in regard to saliva flow, ph, buffer capacity, and colonisation with Streptococcus mutans. In 13 patients the major salivary glands on both sides were included in the treated volume, in seven patients the treatment portals excluded consciously the contralateral major salivary glands. Results: The stimulated saliva flow decreases already during the 1st week of radiotherapy, the decrease follows the dose exponentially; the saliva flow is further reduced in the weeks after the end of treatment. The effect is less pronounced in patients with sparing of contralateral major salivary glands. The majority of patients with unilateral sparing of the major salivary glands retain the baseline value of buffer capacity, whereas buffer capacity of all patients with inclusion of all major salivary glands is markedly reduced with 20 Gy already, without signs of recovery when treatment has stopped. With unilateral salivary gland sparing the pH always remains basic, in bilaterally irradiated patients the pH changes from a mean of 7.3 to 5.8 during treatment. The colonisation with Streptococcus mutans varies little in both groups during the radiotherapy; after the end of therapy, it is higher in bilaterally irradiated patients. Conclusions: The conscious arrangement of irradiation portals in order to spare contralateral major salivary glands in patients with radical radiotherapy of ENT tumors has a significant influence on the oral environment: the stimulated saliva flow is higher, the buffer capacity retains the baseline value, the saliva pH remains basic, and the colonisation with Streptococcus mutans is reduced.Hintergrund: Welchen Einfluss hat das bewusste Aussparen der kontralateralen großen Speicheldrüsen (Glandulae parotis, submandibulares und sublinguales) bei radikaler Strahlentherapie von HNO-Tumoren auf das Milieu der Mundhöhle (Speichel-pH, -Pufferkapazität, -flussrate und Streptococcus-mutans-Kolonisation)? Patienten und Methoden: 20 konsekutive, zustimmende Patienten mit HNO-Tumoren wurden einmal vor, wöchentlich während und 6 Wochen nach Abschluss der Radiotherapie bezüglich Speichelflussrate, pH-Wert, Pufferkapazität des Speichels sowie Kolonisierung mit Streptococus mutans untersucht. Bei 13 Patienten waren alle großen Speicheldrüsen im behandelten Volumen eingeschlossen, bei sieben Patienten sparte die Feldanordnung bewusst die kontralateralen Speicheldrüsen aus. Ergebnisse: Die stimulierbare Speichelmenge nimmt schon während der 1. Woche der Radiotherapie ab, sinkt exponentiell zur Dosis und reduziert sich in den Wochen nach Abschluss der Therapie weiter. Der Effekt ist bei Patienten mit Schonung der kontralateralen großen Speicheldrüsen deutlich geringer ausgeprägt. Die Mehrzahl der Patienten mit einseitiger Schonung hält den Ausgangswert der Pufferkapazität, während alle Patienten mit Einschluss aller großen Speicheldrüsen schon bei Dosen ab 20 Gy erheblich an Pufferkapazität in der Mundhöhle ohne Zeichen der Erholung nach Abschluss der Therapie verlieren. Bei einseitiger Schonung bleibt der Speichel-pH immer basisch; bei beidseitig bestrahlten Patienten sinkt der pH während und nach der Radiotherapie von 7,3 Mittelwert auf 5,8 ab. Die Kolonisierung mit Streptococcus mutans variiert in beiden Patientengruppen während der Radiotherapie wenig; sie ist bei beidseitig bestrahlten Patienten nach Abschluss der Therapie höher als bei Patienten mit Schonung einer Parotis. Schlussfolgerungen: Die bewusste Anordnung der Felder zur Schonung der kontralateralen großen Speicheldrüsen bei Radiotherapie von HNO-Tumoren hat einen signifikanten Effekt auf das Milieu der Mundhöhle: Die stimulierbare Speichelmenge bleibt größer, die Pufferkapazität hält den Ausgangswert, der Speichel-pH bleibt basisch und die Kolonisierung mit Streptococcus mutans bleibt auf dem Niveau des Behandlungsbeginnes.

A microcystic adnexal carcinoma in the auditory canal 15 years after radiotherapy of a 12-year-old boy with nasopharynx carcinoma.

Background:Radiogenic malignancies require cure of the primary disease and a prolonged survival. The introduction of high-volt technology in the 1950s and 1960s made radical radiotherapy feasible and successful in terms of higher cure rates and longer survival. We are already in a time when a higher number of patients with radiogenic secondary malignancies must be expected.Case Report:A 12-year-old boy is reported who suffered from an advanced nasopharynx carcinoma and was treated with radical irradiation in 1983. 15 years later he developed a rare microcystic adnexal carcinoma of the auditory canal inside the volume of the target dose. The secondary malignant neoplasm was resected and required another radiation treatment (1 Gy b.i.d.) due to involved margins.Discussion and Literature Review:The entity of microcystic carcinoma is discussed with a review of the literature on biology, diagnosis, and treatment.Hintergrund:Radiogene Zweittumoren setzen Heilung der Ersterkrankung und langes Überleben voraus. Nach Einführung der Hochvolt-Strahlentherapie in den 50er und 60er Jahren wurden durch kurative Strahlentherapie höhere Heilungsraten und verlängertes Überleben ermöglicht. Wir kommen zu oder sind bereits in einer Zeit, in der mit erhöhter Wahrscheinlichkeit mit dem Auftreten radiogener Zweittumoren gerechnet werden muss.Fallbericht:Berichtet wird über einen Patienten, der 1983 als 12-Jähriger wegen eines lokoregionär fortgeschrittenen Nasopharynxkarzinoms kurativ bestrahlt wurde und bei dem 15 Jahre später ein sehr seltenes mikrozystisches adnexales Karzinom des äußeren Gehörgangs im Volumen der Zieldosis diagnostiziert wurde. Die Zweitneoplasie wurde operiert und erforderte wegen R1-Resektion eine postoperative Radiotherapie (1 Gy b.i.d.).Diskussion und Literaturübersicht:Die Entität des mikrozystischen Karzinoms wird mit einer Literaturübersicht in Bezug auf Biologie, Diagnose und Therapie diskutiert.

Carcinoma of the Oropharynx: Local Failure as the Decisive Parameter for Distant Metastases and Survival

Objective: How important and predicative are clinical parameters and locoregional failure after radical radiotherapy of oropharyngeal carcinomas for the probability of the occurrence of distant metastases? Patients and Methods: From 1 August 1990 to 1 October 1998, 139 patients with carcinomas of the oropharynx were treated in a prospective study by radical radiotherapy and evaluated in regard to the clinical parameters reflex-otalgia, predominant structure of tumor growth, T-category, presence of involved lymph nodes, and smoking and drinking habits. Twenty-nine patients received a concomitant chemotherapy. Twenty-five out of 139 patients had a planned neck dissection after completion of radiotherapy. Ten patients received a salvage operation. Results: The median follow-up time was 24 months (range, 4 to 74). Two- and 5-year overall survival rates according to Kaplan Meier were 56.1 and 49.6%. The tumors were controlled in 77/139 patients (55%). The therapy failed in 62/139 patients (45%). Both groups, 62 patients with locoregional therapy failure and 77 patients with locoregionally controlled tumors, were comparable in regard to performance status (Karnofsky index), age, gender, TNM-categories, histological differentiation, drinking habits, pretherapeutic diagnostics, total dose (Gy), and number of simultaneous chemotherapy cycles. Locoregional tumor control was significantly determined by the parameters reflex-otalgia (p < 0.0078), predominant growth pattern (p < 0.012), T-category (p < 0.03), and smoking (p < 0.0285). The median survival time of patients with locoregional failure is 17 months. At this moment 81% of locoregionally controlled patients are still alive. In 14/62 patients (23%) with locoregional failure, distant metastases were detectable against 4/77 (5%) of locally controlled patients, p < 0.0026. Probability of local control and distant metastases, predominantly pulmonary, reached a plateau after 24 months. Conclusion: Locoregional tumor control, determined by several clinical parameters, is an important parameter for the probability of the development of distant metastases. Failure of local therapy is caused by the biologic aggressiveness of the tumor.Fragestellung: Wie wichtig und wie aussagekräftig sind klinische Parameter und lokoregionäres Therapieversagen nach radikaler Radiotherapie von Oropharynxkarzinomen für die Wahrscheinlichkeit des Auftretens hämatogener Metastasen? Patienten und Methoden: Zwischen 1.8.1990 und 1.10.1998 wurden 139 konsekutive Patienten mit Oropharynxkarzinomen in einer prospektiven Studie mit einer radikalen Radiotherapie behandelt und bezüglich der klinischen Parameter, Reflexotalgie, vorherrschende Struktur des Tumorwachstums, T-Kategorie, Lymphknotenbefall und Genußgewohnheiten untersucht. 29 Patienten erhielten eine begleitende Chemotherapie. Bei 25/139 Patienten wurde entsprechend des Therapiekonzeptes nach abgeschlossener Radiotherapie eine radikale Neck-Dissection vorgenommen. 10/139 Patienten wurden später mit einer “opération de rattrappage” behandelt. Ergebnisse: Der mediane Follow-up betrug 24 Monate (Range 4 bis 74). Zwei- und Fünf-Jahres-Gesamtüberleben nach Kaplan-Meier waren 56,1 und 49,6%. Bei 77/139 (55%) konnte das Leiden lokoregionär kontrolliert werden. Der Tumor wurde bei 62/139 Patienten (45%) nicht beherrscht. Die beiden Patientengruppen, 62 Patienten mit lokalem Therapieversagen und 77 Patienten mit lokal geheiltem Tumorleiden, waren vergleichbar bezüglich Karnofsky-Index, Alter, Geschlecht, histologischer Differenzierung, Alkoholkonsum, prätherapeutischer Diagnostik, Gesamtdosis (Gy) und Anzahl der simultanen Chemotherapiezyklen. Die Tumorkontrolle war von den Parametern Reflexotalgie (p < 0,0078), Wachstumsstruktur (p < 0,012), T-Kategorie (p < 0,03) und Rauchen (p < 0,0285) signifikant mitbestimmt. Die mediane Überlebenszeit der Patienten mit lokoregionärem Therapieversagen betrug 17 Monate. Zu diesem Zeitpunkt lebten noch 81% der lokal kontrollierten Patienten. Bei 23% (14/62) der lokoregionär nicht kontrollierten Patienten wurden Fernmetastasen nachgewiesen, dagegen nur bei 4/77 (5%) der lokoregionär geheilten Patienten (p < 0,0026). Lokale Kontrollwahrscheinlichkeit und Fernmetastasierung, am häufigsten Lungenmetastasen, erreichten ein Plateau nach 24 Monaten. Schlußfolgerungen: Die lokoregionäre Tumorkontrolle, von mehreren klinischen Parametern bestimmt, ist ein entscheidender Hinweis für die Wahrscheinlichkeit der Entstehung von Fernmetastasen. Versagen der Therapie hat seine Ursache in der biologischen Aggressivität des Tumors.