Development and management of severe cutaneous side effects in head-and-neck cancer patients during concurrent radiotherapy and cetuximab.

BACKGROUND: The concurrent administration of cetuximab to radiotherapy has recently been shown to improve the clinical outcome of head-and-neck cancer (HNC) patients. An aggravation of the radiation-induced skin toxicity was not described. Here, however, two cases with severe skin toxicity during the combined treatment are reported. CLINICAL OBSERVATIONS: In a small group of five patients with locally advanced HNC treated with irradiation and concurrent cetuximab, two cases of unusually severe radiation dermatitis were observed. Both patients developed confluent moist desquamations confined to the irradiation field at a dose of 40 Gy (CTC [Common Toxicity Criteria] grade 3), which progressed into an ulcerative dermatitis (grade 4) at 58 Gy and 46 Gy, respectively. Histopathology showed a vacuolic degeneration of basal keratinocytes, subepidermal blister formation, and mixed perivascular and interstitial inflammatory infiltrates leading to a complete loss of the epidermis. These cutaneous side effects led to the discontinuation of radiotherapy. Topical corticosteroids and systemic antibiotic treatment resulted in wound healing, which allowed the continuation of radiotherapy. CONCLUSION: These findings indicate that cetuximab may have the potential to enhance the severity of radiation dermatitis in HNC patients. A systematic monitoring of cutaneous side effects during radiotherapy plus cetuximab is advised in order to reliably estimate the frequency of severe (grade 3/4) radiation dermatitis.

[Radiotherapy of soft tissue sarcoma--part of a multidisciplinary strategy]. / Radiotherapie der Weichteilsarkome--Teil einer multidisziplinären Strategie.

The management of soft tissue sarcoma has evolved from a solitary surgical treatment to an interdisciplinary multimodal approach including radiotherapy. These fundamental changes are the result of increased knowledge in tumor biology, radiation sensitivity and the improvement in modern radiation therapy techniques. A successful effective therapy regimen strongly depends on distinct preoperative diagnostics, preoperative conception of the surgical intervention and an experienced oncological team. Of significant importance for the prognosis is early diagnosis as well as tumor excision with a wide negative margin. However, even after complete wide resection in sano, the use of postoperative radiotherapy can further improve local control and should therefore be applied to the majority of patients. Consequently, radiotherapy should only be omitted in cases in which the tumor has been excised with a very wide negative margin; this implies, however, high quality of surgery and distinct histopathological analysis. Patients with non- or questionable resectable tumors, should be referred for pre-operative radiotherapy in order to improve the surgical results. Recent studies have underlined the efficiency of modern radiotherapy regimens. The different radiotherapy regimens will be highlighted against the background of tumor stage and tumor resectibility.

Tandem high-dose chemotherapy supported by autologous peripheral blood stem-cell transplantation and radiotherapy for recurrent malignant fibrous histiocytoma.

Malignant fibrous histiocytoma (MFH) is a soft-tissue sarcoma created from fibroblast cells and characterized by a high rate of metastasis or recurrence with poor prognosis. We report a case of initially well differentiated (G1) MFH of the trunk in a 33-year-old woman. Two years after primary diagnosis, metastases were found in the lung, trunk, gluteus region, upper extremities and brain. Histopathological findings indicated a stromal tumor consisting of spindle cells, and immunohistochemical examination of resected specimens established the definite diagnosis of poorly differentiated MFH (G3). Initial surgery of several solid tumors on the trunk, lung and extremities was performed. There was a high local recurrence and metastasis rate, and the patient was treated with radiotherapy and conventional chemotherapy followed by tandem high-dose chemotherapy and peripheral blood stem-cell transplantation. She is currently well seven years after the transplant, with no signs of metastasis and recurrence. We review the clinical picture of the tumor in this patient and discuss its diagnosis, pathogenesis and treatment.

Reliable engraftment, low toxicity, and durable remissions following allogeneic blood stem cell transplantation with minimal conditioning.

OBJECTIVE: Allogeneic blood stem cell transplantation (BSCT) can cure patients with hematologic malignancies by high-dose chemotherapy and allogeneic graft-vs-tumor (GvT) reactions. To avoid high-dose conditioning and evaluate engraftment, toxicity, and GvT reactions, we treated a group of high-risk patients with a minimal intensive conditioning regimen followed by allogeneic BSCT. MATERIALS AND METHODS: Thirty-four patients with lymphoma (11), myeloma (10), chronic myeloid leukemia (4), myelodysplastic syndrome (5), and acute myeloid leukemia (4) were treated with fludarabine (3 x 30 mg/m(2)) and 200 cGy total-body irradiation followed by the infusion of peripheral blood stem cells from related (28) or unrelated (6) donors. Cyclosporine or tacrolimus and mycophenolate mofetile were given posttransplant. Most patients had advanced disease, were intensively pretreated, and had contraindications against conventional myeloablative transplantation. RESULTS: Thirty-two patients (94%) had engraftment of donor cells. Patients with lymphatic malignancies developed complete donor chimerism significantly faster than patients with myeloid malignancies (p < 0.05). Clinical responses were observed in 16 of 27 patients (59%) who had active disease at transplantation. Of 7 patients who were treated in remission, 5 remain free of disease. After a median follow-up of 325 days (range 100-844) 22 patients are alive (65%, 14 CR, 4 PR, 4 PD). Two patients (6%) died of treatment-related complications and 10 patients (29%) died of progressive disease. Acute graft-vs-host-disease (GvHD) of grade II or more developed in 17 patients (50%). Chronic GvHD is present in 10 of 22 patients (45%) who are alive beyond day 100. CONCLUSIONS: Toxicity and survival in this group of high-risk patients are superior to those expected with conventional allogeneic transplantation. GvT reactions frequently occur in conjunction with GvHD and can induce durable remissions in patients with advanced hematologic malignancies.

Treatment of secondary myelodysplastic syndrome after heart transplantation with chemotherapy and nonmyeloablative stem-cell transplantation.

BACKGROUND: Treatment of secondary cancer after solid-organ transplantation is difficult because of coexisting medical conditions, reduced organ function, or advanced age in most patients. METHODS: A 60-year-old man developed treatment-related myelodysplastic syndrome (refractory anemia with excess blasts in transformation) 10 years after orthotopic heart transplantation. After remission induction with chemotherapy, the patient received peripheral blood stem cells from his HLA-identical ABO-mismatched (A-->O) sister after conditioning with fludarabine and low-dose total-body irradiation (200 cGy). Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine A. RESULTS: The patient experienced little toxicity from the conditioning regimen and achieved complete donor chimerism within 65 days. Five months after transplant, the patient developed pure red cell aplasia that resolved after treatment. At present, he is alive in complete remission with 100% donor hematopoiesis 940 days after stem-cell transplantation. CONCLUSIONS: Allogeneic blood stem-cell transplantation using minimal conditioning is a new, promising treatment option for patients with hematologic malignancies after solid-organ transplantation.

Dose-volume analysis of radiation nephropathy in children: preliminary report of the risk consortium.

PURPOSE: To characterize kidney function in children and adolescents who had undergone radiation treatment that included parts of the kidney. METHODS AND MATERIALS: Patients receiving radiotherapy during childhood or adolescence were prospectively registered in Germany's Registry for the Evaluation of Side Effects after Radiation in Childhood and Adolescence (RiSK). Detailed information was recorded regarding radiation doses at the organs at risk since 2001 all over Germany. Toxicity evaluation was performed according to standardized Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS: Up to May 2009, 1086 patients from 62 centers were recruited, including 126 patients (median age, 10.2 years) who underwent radiotherapy to parts of the kidneys. Maximal late toxicity (median follow-up 28.5 months in 74 patients) was characterized as Grade 0 (n = 65), 1 (n = 7) or 2 (n = 2). All patients with late effects had received potentially nephrotoxic chemotherapy. A statistically significant difference between patients with and without Grade 1 toxicity, revealing higher exposed kidney volumes in patients with toxicity, was seen for the kidney volume exposed to 20 Gy (V20; p = 0.031) and 30 Gy (V30; p = 0.003). CONCLUSIONS: Preliminary data indicate that radiation-induced kidney function impairment is rare in current pediatric multimodal treatment approaches. In the future, RiSK will be able to provide further detailed data regarding dose-volume effect relationships of radiation-associated side effects in pediatric oncology patients.

Hypothyroidism after head-and-neck radiotherapy in children and adolescents: preliminary results of the "Registry for the Evaluation of Side Effects After Radiotherapy in Childhood and Adolescence" (RiSK).

PURPOSE: The "Registry for the Evaluation of Side Effects After Radiotherapy in Childhood and Adolescence" (RiSK) has been established to prospectively characterize dose-volume effects of radiation in terms of side effects. The aim of this analysis was to characterize the function of the thyroid gland after radiotherapy to the head-and-neck region in children and adolescents. METHODS AND MATERIALS: Detailed information regarding radiation doses to at-risk organs has been collected across Germany since 2001. Thyroid function was evaluated by blood value examinations of thyroid-stimulating hormone, triiodothyronine, and thyroxine. Information regarding thyroid hormone substitution was requested from the treating physicians. RESULTS: Until May 2009, 1,086 patients from 62 centers were recruited, including 404 patients (median age, 10.9 years) who had received radiotherapy to the thyroid gland and/or hypophysis. Follow-up information was available for 264 patients (60.9%; median follow-up, 40 months), with 60 patients (22.7%) showing pathologic values. In comparison to patients treated with prophylactic cranial irradiation (median dose, 12 Gy), patients with radiation doses of 15 to 25 Gy to the thyroid gland had a hazard ratio of 3.072 (p=0.002) for the development of pathologic thyroid blood values. Patients with greater than 25 Gy to the thyroid gland and patients who underwent craniospinal irradiation had hazard ratios of 3.768 (p=0.009) and 5.674 (p<0.001), respectively. The cumulative incidence of thyroid hormone substitution therapy did not differ between defined subgroups. CONCLUSIONS: Radiation-induced thyroid function impairment, including damage to the thyroid gland and/or hypophysis, can frequently be observed after radiotherapy in children. A structured follow-up examination is advised.

Acute toxicity profile of radiotherapy in 690 children and adolescents: RiSK data.

BACKGROUND AND PURPOSE: The "Registry for the evaluation of side effects after radiation in childhood and adolescence" (risk) was introduced to characterize adverse effects of radiotherapy in childhood and adolescence prospectively. The aim of this analysis was to characterize the pattern of acute side effects. MATERIALS AND METHODS: Since 2001, patients receiving radiotherapy in one of the German pediatric therapy trials have been registered in RiSK with detailed information regarding radiation doses to organs at risk and characterization of acute toxicities. RESULTS: From 2001 to May 2009, 690 patients have been characterized for acute toxicity in primary therapy. Acute toxicity ≥ grade 1 was observed in 506 patients. In patients irradiated in their lung and liver, patients with grade 1 or 2 acute toxicities showed higher organ volumes exposed to radiation doses <20 Gray (Gy) compared to patients without toxicities. For the salivary glands, there was a positive correlation between the acute toxicity grade and the maximum radiation dose to the organ; the lower GI tract showed a similar trend. The impact of different chemotherapy regimens on these acute side effects remains unclear. Age did not have any impact on side effects. CONCLUSION: This analysis gives a comprehensive overview of the acute toxicities of radiotherapy in children and adolescents. With prolongation of follow-up, detailed analyses regarding late toxicities will be possible with the characterization of dose-volume-effect relationships.

Study protocol of the German "Registry for the detection of late sequelae after radiotherapy in childhood and adolescence" (RiSK).

BACKGROUND: Late effects after radiotherapy in childhood and adolescence have mainly been characterized retrospectively with small patient numbers. However, these analyses are limited due to little information regarding organ dose levels in many cases. To overcome this limitation, the German Group of Paediatric Radiation Oncology (APRO) established the "Registry for the evaluation of late side effects after radiation in childhood and adolescence" (RiSK). The study protocol and the documentation forms are given in this publication. METHODS/DESIGN: Radiation parameters including detailed organ doses as well as toxicity evaluations are collected prospectively from centres all over Germany. Standardized documentation forms are used. These forms are given in an English and German version as additional files to this publication. Documentation is planned for all children who receive radiotherapy in one of the therapy trials of the "German Society of Paediatric Oncology and Haematology (GPOH)". The study started in a pilot phase in June 2001 in few centres. Since 2004 documentation has been performed all over Germany and is still on-going. DISCUSSION: To our knowledge, "RiSK" is the only multi-centre study that evaluates radiation associated side effects prospectively with detailed information about organ dose levels. With ongoing recruitment and prolongation of follow-up powerful data will be obtained in a few years. A broad use and international cooperation are welcome.

[Therapy-associated late effects after irradiation of malignant diseases in childhood and adolescence. Feasibility analyses of a prospective multicenter register study]. / Behandlungsassoziierte Spätfolgen nach Strahlentherapie maligner Erkrankungen im Kindes- und Jugendalter : Machbarkeitsanalyse einer prospektiven multizentrischen Registerstudie.

BACKGROUND AND PURPOSE: Radiogenic late effects in children and adolescents have been evaluated retrospectively in most analyses, with small patient numbers. The German Group of Pediatric Radiation Oncology (APRO) has generated a concept for a prospective evaluation of radiation-associated late effects in childhood. The aim of this study was to evaluate the feasibility of a nationwide central database for the documentation of radiation parameters and side effects of all children treated within therapy protocols of the German Society of Pediatric Oncology and Hematology (GPOH). PATIENTS AND METHODS: A study center has been implemented in Muenster, the documentation has started in July 2001 in few centers in a pilot phase. Since February 2004 the documentation is done countrywide. Detailed documentation forms have been designed for treatment parameters and for doses applied at organs at risk. Furthermore, a uniform toxicity documentation, according to the RTOG/EORTC criteria, was chosen. Patients were reported from the study centers of the GPOH to the study center. All information was collected and analyzed in the study center. RESULTS: Till July 31, 2005, 438 documentations of radiation and 579 toxicity documentations of side effects have been collected in the study center. 46 centers for radiotherapy in Germany and one center each in Austria and in Switzerland took part in the documentation. The quality of documentation regarding completeness and plausibility fulfilled the expected criteria in most cases. This feasibility analysis showed that important information about organ dose levels and side effects was documented in a large number of patients (Figures 1 and 2). CONCLUSION: This prospective evaluation of radiotherapy and radiogenic side effects in children and adolescents will allow correlating doses at organs at risk and the incidence of acute and late sequelae in Germany. Further documentations and a longer follow-up are necessary to obtain powerful results.