The impact of local control on overall survival after stereotactic body radiotherapy for liver and lung metastases from colorectal cancer: a combined analysis of 388 patients with 500 metastases.

BACKGROUND: The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer. METHODS: The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS. RESULTS: Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC. CONCLUSION: In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months.

Stereotactic body radiotherapy (SBRT) for multiple pulmonary oligometastases: Analysis of number and timing of repeat SBRT as impact factors on treatment safety and efficacy.

BACKGROUND: Stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by an excellent safety profile; however, experiences are mostly based on treatment of one single metastasis. It was the aim of this study to evaluate safety and efficacy of SBRT for multiple pulmonary metastases. PATIENTS AND METHODS: This study is based on a retrospective database of the DEGRO stereotactic working group, consisting of 637 patients with 858 treatments. Cox regression and logistic regression were used to analyze the association between the number of SBRT treatments or the number and the timing of repeat SBRT courses with overall survival (OS) and the risk of early death. RESULTS: Out of 637 patients, 145 patients were treated for multiple pulmonary metastases; 88 patients received all SBRT treatments within one month whereas 57 patients were treated with repeat SBRT separated by at least one month. Median OS for the total patient population was 23.5 months and OS was not significantly influenced by the overall number of SBRT treatments or the number and timing of repeat SBRT courses. The risk of early death within 3 and 6 months was not increased in patients treated with multiple SBRT treatments, and no grade 4 or grade 5 toxicity was observed in these patients. CONCLUSIONS: In appropriately selected patients, synchronous SBRT for multiple pulmonary oligometastases and repeat SBRT may have a comparable safety and efficacy profile compared to SBRT for one single oligometastasis.

Nomogram based overall survival prediction in stereotactic body radiotherapy for oligo-metastatic lung disease.

BACKGROUND: Radical local treatment of pulmonary metastases is practiced with increasing frequency due to acknowledgment and better understanding of oligo-metastatic disease. This study aimed to develop a nomogram predicting overall survival (OS) after stereotactic body radiotherapy (SBRT) for pulmonary metastases. PATIENTS AND METHODS: A multi-institutional database of 670 patients treated with SBRT for pulmonary metastases was used as training cohort. Cox regression analysis with bidirectional variable elimination was performed to identify factors to be included into the nomogram model to predict 2-year OS. The calibration rate of the nomogram was assessed by plotting the actual Kaplan-Meier 2-year OS against the nomogram predicted survival. The nomogram was externally validated using two separate monocentric databases of 145 and 92 patients treated with SBRT for pulmonary metastases. RESULTS: The median follow up of the trainings cohort was 14.3months, the 2-year and 5-year OS was 52.6% and 23.7%, respectively. Karnofsky performance index, type of the primary tumor, control of the primary tumor, maximum diameter of the largest treated metastasis and number of metastases (1 versus >1) were significant prognostic factors in the Cox model (all p<0.05). The calculated concordance-index for the nomogram was 0.73 (concordance indexes of all prognostic factors between 0.54 and 0.6). Based on the nomogram the training cohort was divided into 4 groups and 2-year OS ranged between 24.2% and 76.1% (predicted OS between 30.2% and 78.4%). The nomogram discriminated between risk groups in the two validation cohorts (concordance index 0.68 and 0.67). CONCLUSIONS: A nomogram for prediction of OS after SBRT for pulmonary metastases was generated and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting. KEY MESSAGE: A nomogram for prediction of overall survival after stereotactic body radiotherapy (SBRT) for pulmonary metastases was developed and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting.

Sentinel node biopsy by indocyanine green retention fluorescence detection for inguinal lymph node staging of anal cancer: preliminary experience.

BACKGROUND: There is some evidence that sentinel lymph node (SLN) biopsy guided by dye injection and/or radioisotopes can improve staging of inguinal lymph nodes (LNs) in anal cancer. This study was performed to investigate the feasibility of fluorescence detection of SLN and lymphatic mapping in anal cancer. METHODS: Twelve patients with anal cancer without evidence for inguinal LN involvement were included in the study. Intraoperatively, all patients received a peritumorous injection of 25 mg indocyanine green (ICG) for fluorescence imaging of the SLN with a near-infrared camera. For comparison, conventional SLN detection by technetium-(99)m-sulfur radiocolloid injection in combination with blue dye was also performed in all patients. The results of both techniques and the effect on the therapeutic regimen were analyzed. RESULTS: Overall, ICG fluorescence imaging identified at least one SLN in 10 of 12 patients (detection rate, 83%). With the combination of radionuclide and blue dye, SLN were detected in 9 of 12 patients (detection rate, 75%). Metastatic involvement of the SLN was found in 2 of 10 patients versus 2 of 9 patients. Patients with metastatic involvement of the SLN received extended radiation field with inguinal boost. CONCLUSIONS: ICG fluorescence imaging allows intraoperative lymphatic mapping and transcutaneous SLN detection for selective biopsy of inguinal SLN in anal cancer. This technique should be further evaluated in comparative studies with larger patient numbers.

Results of European pooled analysis of IORT-containing multimodality treatment for locally advanced rectal cancer: adjuvant chemotherapy prevents local recurrence rather than distant metastases.

BACKGROUND: The purpose of this study is to analyze the pooled results of multimodality treatment of locally advanced rectal cancer (LARC) in four major treatment centers with particular expertise in intraoperative radiotherapy (IORT). PATIENTS AND METHODS: A total of 605 patients with LARC who underwent multimodality treatment up to 2005 were studied. The basic treatment principle was preoperative (chemo)radiotherapy, intended radical surgery, IORT and elective adjuvant chemotherapy (aCT). In uni- and multivariate analyses, risk factors for local recurrence (LR), distant metastases (DM) and overall survival (OS) were studied. RESULTS: Chemoradiotherapy lead to more downstaging and complete remissions than radiotherapy alone (P < 0.001). In all, 42% of the patients received aCT, independent of tumor-node-metastasis stage or radicality of the resection. LR rate, DM rate and OS were 12.0%, 29.2% and 67.1%, respectively. Risk factors associated with LR were no downstaging, lymph node (LN) positivity, margin involvement and no postoperative chemotherapy. Male gender, preoperatively staged T4 disease, no downstaging, LN positivity and margin involvement were associated with a higher risk for DM. A risk model was created to determine a prognostic index for individual patients with LARC. CONCLUSIONS: Overall oncological results after multimodality treatment of LARC are promising. Adding aCT to the treatment can possibly improve LR rates.

[Solitary extramedullary plasmocytoma of the conjunctiva]. / Isoliertes extraossäres Plasmozytom der Konjunktiva.

There is a wide variety of conjunctival tumors. A good diagnosis can be reached by discussing the case history with the patient in conjunction with a slit-lamp examination. Presented here is the case of a 39-year-old patient with a rapidly growing conjunctival tumor on his left eye. After tumor resection and histological analysis, a plasmacytoma was found. The completed hemato-oncological analysis gave no further suspicious pathological results, leading to the diagnosis of a solitary extramedullary plasmacytoma. Percutaneous radiotherapy was carried out.

Diffusion tensor imaging screening of radiation-induced changes in the white matter after prophylactic cranial irradiation of patients with small cell lung cancer: first results of a prospective study.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) will show abnormal fractional anisotropy (FA) in the normal-appearing brain after prophylactic cranial irradiation (PCI). These abnormalities will be more accentuated in patients with underlying vascular risk factors. MATERIALS AND METHODS: A prospective study by use of DTI and conventional T2-weighted MR images was performed with a 1.5T unit with 16 patients with small cell lung cancer and undergoing PCI. All of the T2-weighted images were evaluated with respect to abnormalities in signal intensity of white matter as markers of radiation damage. Measurements of FA were performed before, at the end of, and 6 weeks after radiation therapy. On the FA maps, the bifrontal white matter, the corona radiata, the cerebellum, and the brain stem were evaluated. FA values were compared with respect to age, demographic, and vascular risk factors. Statistical analyses (Friedman test, Wilcoxon test, and Mann-Whitney U test) were performed. RESULTS: Fractional anisotropy decreased significantly in supratentorial and infratentorial normal-appearing white matter from the beginning to the end of PCI (P < .01). A further decline in FA occurred 6 weeks after irradiation (P < .05). A stronger reduction in FA was observed in patients with more than 1 vascular risk factor. There was an age-related reduction of white matter FA. Patients 65 years and older showed a trend toward a stronger reduction in FA. CONCLUSION: During the acute phase, after PCI, patients with many vascular risk factors showed stronger damage in the white matter compared with patients with only 1 risk factor.

Indolent stage IE non-Hodgkin's lymphoma of the orbit: results after primary radiotherapy.

AIMS: Primary non-Hodgkin's lymphoma (NHL) of the orbit is uncommon, representing approximately 8% of extranodal NHLs. Twenty-two patients with indolent stage IE NHL were reviewed retrospectively to analyze the outcome and late effects of primary local radiotherapy. MATERIALS AND METHODS: The median age at first diagnosis was 63.5 years (range 24-82 years). Extranodal mucosa-associated lymphoid tissue lymphoma (n = 15) was the most common histological subtype of NHL, followed by follicular (n = 6) and lymphoplasmacytic lymphoma (n = 1). Radiotherapy was performed using a linear accelerator. The median radiation dose was 40 Gy (range 30-46 Gy). None of the patients received chemotherapy before irradiation. The follow-up period was 62 months (range 8-136 months). RESULTS: A complete response was achieved in all patients. The 5-year local control rate was 100%. Distant relapse occurred in 2 patients, resulting in a 5-year distant relapse-free survival rate of 88%. The 5-year overall survival rate was 89%; there were no lymphoma-related deaths. No serious acute complications (grade 3/4) were observed. Grade 1/2 late effects were documented in 44% of patients. Grade 3 complications (cataract: 2, dryness: 2) were observed in 4 patients (18%). CONCLUSIONS: Indolent early stage orbital NHL can be controlled with local radiotherapy. Morbidity is low. Regular follow-up examinations are necessary to detect rare cases of distant relapse.

Potential target antigens for immunotherapy in human pancreatic cancer.

BACKGROUND: To be effective and selective, immunotherapy ideally targets specifically tumor cells and spares normal tissues. Identification of tumor specific antigens is a prerequisite to establish an effective immunotherapy. Still very little is known about the expression of tumor-related antigens in pancreatic neoplasms. Cancer Testis antigens (CT) are antigens shared by a variety of malignant tumors, but not by normal tissues with the exception of germ cells in testis. Restricted expression in neoplastic tissues and inherent immunogenic features make CT antigens ideal for use in immunotherapy. We analyzed the expression of a selected panel of nine CT antigens that have been proven to elicit an efficient immunogenic response in other malignancies. In addition we analyzed the expression of HERV-K-MEL, an immunogenic antigen of viral origin. METHODS: Pancreatic adenocarcinoma tumor samples (n=130) were obtained intraoperatively, control tissues (n=23) were collected from cadaveric donor and from patients with chronic pancreatitis. Tumor-associated antigen expression of MAGE-A1, MAGE-A3, MAGE-A4, MAGE-A10, LAGE-1, NY-ESO-1, SCP-1, SSX-2, SSX-4 and HERV-K-MEL was assessed by PCR. Sequencing of PCR products were performed to assess the expression of SSX-4 in neoplastic and normal pancreatic tissues. RESULTS: Three of 10 tested antigens were expressed in over 10% of malignant pancreatic tissue samples. SSX-4 was found positive in 30% of cases, SCP-1 in 19% and HERV-K-MEL in 23% of cases. No expression of CT antigens was found in non-malignant pancreatic tissue with the exception of SSX-4 and and SSX-2. CONCLUSIONS: Fifty two percentage of the analyzed tissues expressed at least one CT antigen. The concomitant expression of SSX-4 in both malignant and non-malignant pancreatic tissue is a new finding which may raise concerns for immunotherapy. However, HERV-K-MEL is expressed with a relatively high prevalence and may be a candidate for specific immunotherapy in a large subgroup of pancreatic cancer patients. This study advocates the analysis of patients with regard to their immunogenic profile before the onset of antigen-specific immunotherapy.

[Advances in radio-oncology. From precision radiotherapy with photons to ion therapy with protons and carbon ions]. / Fortschritte in der Radioonkologie. Von der Präzisionsstrahlentherapie mit Photonen zur Ionentherapie mit Protonen und Kohlenstoffionen.

Modern techniques in radiation oncology, such as fractionated stereotactic radiotherapy (FSRT), stereotactic radiosurgery (SRS) or intensity modulated radiotherapy (IMRT) allow the application of high local doses to defined treatment volumes, while normal structures in close vicinity can be spared; high local control rates can be achieved, while treatment-related toxicity can be minimized. Innovative Hi-Art tomotherapy systems offer an alternative, combining a 6 MV photon accelerator with a CT scanner. Ion beams, such as protons and carbon ions, have been shown to be beneficial for distinct tumor entities. Both offer a characteristic physical dose distribution with an inverse dose profile contributing to beneficial dose conformality. Carbon ions also offer the advantage of increased relative biological effectiveness. For certain tumor types, a significant increase in local control and survival rates could be obtained with carbon ions.

Treatment of non-small cell lung cancer with intensity-modulated radiation therapy in combination with cetuximab: the NEAR protocol (NCT00115518).

BACKGROUND: Even today, treatment of Stage III NSCLC still poses a serious challenge. So far, surgical resection is the treatment of choice. Patients whose tumour is not resectable or who are unfit to undergo surgery are usually referred to a combined radio-chemotherapy. However, combined radio-chemotherapeutic treatment is also associated with sometimes marked side effects but has been shown to be more efficient than radiation therapy alone. Nevertheless, there is a significant subset of patients whose overall condition does not permit administration of chemotherapy in a combined-modality treatment. It could be demonstrated though, that NSCLCs often exhibit over-expression of EGF-receptors hence providing an excellent target for the monoclonal EGFR-antagonist cetuximab (Erbitux) which has already been shown to be effective in colorectal as well as head-and-neck tumours with comparatively mild side-effects. METHODS/DESIGN: The NEAR trial is a prospective phase II feasibility study combining a monoclonal EGF-receptor antibody with loco-regional irradiation in patients with stage III NSCLC. This trial aims at testing the combination's efficacy and rate of development of distant metastases with an accrual of 30 patients. Patients receive weekly infusions of cetuximab (Erbitux) plus loco-regional radiation therapy as intensity-modulated radiation therapy. After conclusion of radiation treatment patients continue to receive weekly cetuximab for 13 more cycles. DISCUSSION: The primary objective of the NEAR trial is to evaluate toxicities and feasibility of the combined treatment with cetuximab (Erbitux) and IMRT loco-regional irradiation. Secondary objectives are remission rates, 3-year-survival and local/systemic progression-free survival.

Clinical application of cone beam digital volume tomography in children with cleft lip and palate.

OBJECTIVES: The diagnostic advantages of digital volume tomography (DVT) over conventional imaging and computed tomography are demonstrated in terms of the respective radiation exposure. The potential role for three-dimensional imaging in cleft lip and palate patients is illustrated on the basis of clinical examples. METHODS: The radiation exposure resulting from scans using a cone beam DVT (NEW TOM QR-DVT 9000, Marburg, Germany) was measured with an Alderson-Rando-Phantom (The Phantom Laboratory, New York, NY) and compared with that resulting from other standard imaging modalities. The patient sample consisted of young children with cleft lip and palate on whom orthodontic and surgical treatment was planned on an interdisciplinary basis at the University-Hospital of Heidelberg. RESULTS: Digital volume tomography allows high-quality three-dimensional imaging of the premaxilla region, with an effective equivalent investigation dose of (110 kV, 5.4 mA) 0.342 mSv based on ICRP recommendations. While the effective equivalent investigation dose for DVT is higher than that for standard imaging techniques (for example digital panoramic radiograph Orthophos Plus DS Ceph (66 kV, 8 mA) 0.016 mSv), it is much lower than that for a normal CT scan (e.g. Picker International Inc., Highland Heights, OH) adjusted at (spiral 130 kV, 125 mA, and 30 mA, 1.5 s) 2.27 mSv. Digital volume tomography provides extensive data important in clinical decision making. CONCLUSIONS: The clinical examples show the good applicability of DVT with a reduced radiation dose.

Piezosurgery--a new safe technique in cranial osteoplasty?

All surgical interventions on the neurocranium bear the risk of injury of the dura mater and development of a cerebrospinal fluid fistula. Therefore, despite careful preparation, damage to the dura mater cannot always be omitted. Especially after surgery and in patients with increased intracranial pressure (craniosynostoses) there is a high risk of perforating the dura. In this article a new surgical technique for osteotomy (Piezosurgery) that avoids perforation of the dura is presented. Ultrasonic microvibrations allow a selective cut of only mineralized structures without damage to the soft tissue. Even in case of accidental contact the dura remains undamaged. This advantage is also useful for bone splitting, to separate the tabula externa from the tabula interna in situ, without any risk of dura perforation even in case of the very thin bones in an infantile skull. The present work shows the applicability of piezoelectric surgery in high-risk patients after osteotomy, avoiding perforation of the dura mater.

Neoadjuvant chemoradiation in patients with pancreatic adenocarcinoma.

In spite of the high mortality in pancreatic cancer, significant progress is being made. This review discusses multimodality therapy for patients with pancreatic cancer. Surgical therapy currently offers the only potential monomodal cure for pancreatic adenocarcinoma. However, only 10-20% of patients present with tumors that are amenable to resection, and even after resection of localized cancers, long-term survival is rare. The addition of chemoradiation therapy significantly increases median survival. To achieve long-term success in treating this disease it is therefore increasingly important to identify effective neoadjuvant/adjuvant multimodality therapies. Preoperative chemoradiation for potentially resectable pancreatic cancer has the following advantages: (1) neoadjuvant treatment would eliminate the delay of adjuvant treatment due to postoperative complications; (2) neoadjuvant treatment could avoid unnecessary surgery for patients with metastatic disease evident on restaging after neoadjuvant therapy; (3) down-staging after neoadjuvant therapy may increase the likelihood of negative surgical margins; and (4) neoadjuvant treatment could prevent peritoneal tumor cell implantation and dissemination caused during surgery. This review systematically summarizes the current status, controversies, and prospects of neoadjuvant treatment of pancreatic cancer.

Randomized phase II--study evaluating EGFR targeting therapy with cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer--PARC: study protocol [ISRCTN56652283].

BACKGROUND: Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. METHODS/DESIGN: The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrollment. DISCUSSION: The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.

Phase III trial of postoperative cisplatin, interferon alpha-2b, and 5-FU combined with external radiation treatment versus 5-FU alone for patients with resected pancreatic adenocarcinoma -- CapRI: study protocol [ISRCTN62866759].

UNLABELLED: After surgical intervention with curative intention in specialised centres the five-year survival of patients with carcinoma of the exocrine pancreas is only 15%. The ESPAC-1 trial showed an increased five-year survival of 21% achieved with adjuvant chemotherapy. Investigators from the Virginia Mason Clinic have reported a 5-year survival rate of 55% in a phase II trial evaluating adjuvant chemotherapy, immunotherapy and external-beam radiation. DESIGN: The CapRI study is an open, controlled, prospective, randomised multi-centre phase III trial. Patients in study arm A will be treated as outpatients with 5-Fluorouracil; Cisplatin and 3 million units Interferon alpha-2b for 5 1/2 weeks combined with external beam radiation. After chemo-radiation the patients receive continuous 5-FU infusions for two more cycles. Patients in study arm B will be treated as outpatients with intravenous bolus injections of folinic acid, followed by intravenous bolus injections of 5-FU given on 5 consecutive days every 28 days for 6 cycles. A total of 110 patients with specimen-proven R0 or R1 resected pancreatic adenocarcinoma will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patients' enrollment. DISCUSSION: The aim of this study is to evaluate the overall survival period attained by chemo-radiotherapy including interferon alpha 2b administration with adjuvant chemotherapy. The influence of interferon alpha on the effectiveness of the patients' chemoradiation regimen, the toxicity, the disease-free interval and the quality of life are analysed. Different factors are tested in terms of their potential role as predictive markers.