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1.  The prognostic value of tumor necrosis in patients undergoing stereotactic radiosurgery of brain metastases 
This retrospective study investigated the outcome of patients with brain metastases after radiosurgery with special emphasis on prognostic impact of visible intratumoral necrosis on survival and local control.
From 1998 through 2008, 149 patients with brain metastases from solid tumors were treated with stereotactic radiotherapy at Luebeck University. Median age was 58.4 years with 11%, 78%, 10% in recursive partitioning analysis (RPA) classes I, II, III, respectively. 70% had 1 metastasis, 29% 2-3 metastases, 2 patients more than 3 metastases, 71% active extracranial disease. Median volume of metastatic lesions was 4.7 cm3, median radiosurgery dose 22 Gy (single fraction). 71% of patients received additional whole-brain irradiation (WBI). All patients were analyzed regarding survival, local, distant failure and prognostic factors, side effects and changes in neurologic symptoms after radiotherapy. The type of contrast-enhancement in MR imaging was also analyzed; metastatic lesions were classified as containing necrosis if they appeared as ring-enhancing with central areas of no or minimal contrast enhancement.
Median survival was 7.0 months with 1-year and 5-year survival rates of 33% and 0.4%, respectively. Tumor necrosis (ring-enhancement) was visible on pretreatment MRI scans in 56% of all lesions and lesions with necrosis were larger than non-necrotic lesions (6.7 cm3 vs. 3.2 cm3, p = 0.01). Patients with tumor necrosis had a median survival of 5.4 months, patients without tumor necrosis 7.2 months. Local control rate in the irradiated volume was 70%, median survival without local failure 17.8 months. Control in the brain outside the irradiated volume was 60%, median survival without distant failure 14.0 months. Significant prognostic factors for overall survival were KPS (p = 0.001), presence of tumor necrosis on pretreatment MRI (p = 0.001) with RPA-class and WBI reaching marginal significance (each p = 0.05). Prognostic impact of tumor necrosis remained significant if only smaller tumors with a volume below 3.5 cm3 (p = 0.03). Side effects were rare, only one patient suffered from serious acute side effects.
Results of this retrospective study support that stereotactic radiotherapy is an effective treatment option for patients with metastatic brain lesions. The prognostic impact of visible tumor necrosis (ring-enhancement) on pretreatment MRI scans should be further investigated.
PMCID: PMC3707781  PMID: 23822663
Radiotherapy; Stereotactic radiotherapy; Brain metastasis; Prognostic factor; Necrosis
2.  Phase II trial of preoperative radiochemotherapy with concurrent bevacizumab, capecitabine and oxaliplatin in patients with locally advanced rectal cancer 
Preoperative radiochemotherapy (RCT) with 5-FU or capecitabine is the standard of care for patients with locally advanced rectal cancer (LARC). Preoperative RCT achieves pathological complete response rates (pCR) of 10-15%. We conducted a single arm phase II study to investigate the feasibility and efficacy of addition of bevacizumab and oxaliplatin to preoperative standard RCT with capecitabine.
Eligible patients had LARC (cT3-4; N0/1/2, M0/1) and were treated with preoperative RCT prior to planned surgery. Patients received conventionally fractionated radiotherapy (50.4 Gy in 1.8 Gy fractions) and simultaneous chemotherapy with capecitabine 825 mg/m2 bid (d1-14, d22-35) and oxaliplatin 50 mg/m2 (d1, d8, d22, d29). Bevacizumab 5 mg/kg was added on days 1, 15, and 29. The primary study objective was the pCR rate.
70 patients with LARC (cT3-4; N0/1, M0/1), ECOG < 2, were enrolled at 6 sites from 07/2008 through 02/2010 (median age 61 years [range 39–89], 68% male). At initial diagnosis, 84% of patients had clinical stage T3, 62% of patients had nodal involvement and 83% of patients were M0. Mean tumor distance from anal verge was 5.92 cm (± 3.68). 58 patients received the complete RCT (full dose RT and full dose of all chemotherapy). During preoperative treatment, grade 3 or 4 toxicities were experienced by 6 and 2 patients, respectively: grade 4 diarrhea and nausea in one patient (1.4%), respectively, grade 3 diarrhea in 2 patients (3%), grade 3 obstipation, anal abscess, anaphylactic reaction, leucopenia and neutropenia in one patient (1.4%), respectively. In total, 30 patients (46%) developed postoperative complications of any grade including one gastrointestinal perforation in one patient (2%), wound-healing problems in 7 patients (11%) and bleedings in 2 patients (3%). pCR was observed in 12/69 (17.4%) patients. Pathological downstaging (ypT < cT and ypN ≤ cN) was achieved in 31 of 69 patients (44.9%). All of the 66 operated patients had a R0 resection. 47 patients (68.1%) underwent sphincter preserving surgery.
The addition of bevacizumab and oxaliplatin to RCT with capecitabine was well tolerated and did not increase perioperative morbidity or mortality. However, the pCR rate was not improved in comparison to other trials that used capecitabine or capecitabine/oxaliplatin in preoperative radiochemotherapy.
PMCID: PMC3679876  PMID: 23587311
Bevacizumab; Rectal cancer; Preoperative radiochemotherapy; Capecitabine; Oxaliplatin
3.  Does Radiotherapy Have Curative Potential in Metastatic Patients? The Concept of Local Therapy in Oligometastatic Breast Cancer 
Breast Care  2011;6(5):363-368.
In 1995, Hellmann and Weichselbaum defined for the first time the term oligometastases which is used to describe limited metastasis with a maximum of 3–4 clinically detectable metastases. It is assumed that these patients have a better prognosis and that local treatment of the metastases plays a significant part in the further development of the disease. Therefore, these patients could benefit from a curative local therapy of the manifested metastases. Local therapy measures include mainly radiotherapeutic methods alongside invasive ablative processes, such as surgical resection and radiofrequency ablation. Patients subjected to radiation therapy benefit especially from the usage of modern precision technology as it reduces the radiation exposure to the normal tissue, and because short radiation sessions with escalating doses are possible (e.g. radiation surgery, image-assisted radiation therapy, stereotactic radiation). Initial clinical studies show very good local tumor control rates which are on a par with resection and ablative methods, but with very few side effects and risks. This article summarizes the integration of the concept of oligometastases in the radiotherapy of limited metastatic breast cancer.
PMCID: PMC3357150  PMID: 22619646
Breast cancer; Oligometastases; Radiotherapy; Stereotactic body radiotherapy, SBRT
4.  Margins! Margins. Margins? How Important Is Margin Status in Breast-Preserving Therapy? 
Breast Care  2011;6(5):359-362.
Margin status is surely a prognostic factor in patients undergoing breast-conserving therapy, but its impact is probably overestimated in case of adequate adjuvant radiotherapy. Radiotherapy improves local control after excision of the primary tumor in all subgroups of patients. There is, in contrast, no evidence that a certain margin width or a re-resection improves local control.
PMCID: PMC3357154  PMID: 22619645
Breast cancer; Breast preservation; Margins; Surgery; Radiotherapy
5.  EGF61 polymorphism predicts complete pathologic response to cetuximab-based chemoradiation independent of KRAS status in locally advanced rectal cancer patients 
Cetuximab has demonstrated significant clinical activity in metastatic colon cancer. However, cetuximab-containing neoadjuvant chemoradiation has not been shown to improve tumor response in locally advanced rectal cancer patients in recent phase I/II trials. We evaluated functional germline polymorphisms of genes involved in EGFR pathway, angiogenesis, ADCC, DNA repair, and drug metabolism, for their potential role as molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation.
130 patients (74 men and 56 women) with locally advanced rectal cancer (4 with stage II, 109 with stage III and 15 with stage IV, 2 unknown) who were enrolled in phase I/II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was performed using PCR-RFLP assays. Fisher’s exact test was used to examine associations between polymorphisms and complete pathologic response (pCR) that was determined by a modified Dworak classification system (grade 0-III vs grade IV: complete response).
Patients with the EGF 61 G/G genotype had pCR of 45% (5/11), compared with 21% (11/53) in patients heterozygous, and 2% (1/54) in patients homozygous for the A/A allele (P <0.001). In addition, this association between EGF 61 G allele and pCR remained significant (p=0.019) in the 59 patients with wild type KRAS.
This study suggests EGF A+61G polymorphism to be a predictive marker for pCR, independent of KRAS mutation status, to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer.
PMCID: PMC3149732  PMID: 21673069
colorectal cancer; EGF 61; complete pathologic response (pCR); KRAS; cetuximab
6.  Concurrent chemoradiation of metastases with capecitabine and oxaliplatin and 3D-CRT in patients with oligometastatic colorectal cancer: results of a phase I study 
Local control appears to be an important treatment aim in patients with limited metastases (oligometastases) of colorectal cancer (CRC). Those patients show a favourable prognosis, if - in addition to the local effective treatment - an occurrence of new metastases may also be postponed by effective systemic therapy. The purpose of this dose escalation phase I study was to establish the efficacy of local radiotherapy (RT) of oligometastatic CRC with a concurrent standard chemotherapy regimen.
Patients with first-, second- or third-line therapy of oligometastatic CRC (1–3 metastases or local recurrence plus max. 2 metastases) received capecitabine (825 mg/m2/d BID d 1–14; 22–35) and oxaliplatin (50 mg/m2 d 1, 8, 22, 29). 3D-conformal RT of all metastatic lesions was delivered in 2.0 Gy up to 36 Gy to 50 Gy (3 dose levels). Primary endpoint was the maximal tolerable dose (MTD) of RT defined as the level at which two or more of six patients experienced dose-limiting toxicity (DLT).
Between 09/2004 and 08/2007, 9 patients (7 male, 2 female, 50–74 years) were enrolled, 6 patients treated at dose level 1 (36 Gy), 3 patients at dose level 2 (44 Gy). 1 patient from the first cohort experienced DLT (oxaliplatin-related hypersensitivity reaction). No radiation-induced DLT occurred. 6/9 patients achieved objective response (partial remission). One year after initiation, all patients were alive, 6 patients survived (16 to 54 months) patients died of tumor progression (14 to 23 months). The phase II part of the trial had to be closed due to recruitment failure.
Local 3D-CRT to metastatic lesions in addition to standard chemotherapy was feasible, DLT was not documented. 3/9 patients survived for a period of 3.5 to 4.4 years (time at the last evaluation). Radiotherapy of metastatic lesions should be incorporated into subsequent trials.
PMCID: PMC3403841  PMID: 22681700
Oligometastatic colorectal cancer; Chemoradiation; Capecitabine; Oxaliplatin; Phase I study

Results 1-6 (6)