Adjuvant hypofractionated radiotherapy with simultaneous integrated boost after breast-conserving surgery: results of a prospective trial.

PURPOSE: We report results of a multicenter prospective single-arm phase II trial (ARO-2013-04, NCT01948726) of moderately accelerated hypofractionated radiotherapy with a simultaneous integrated boost (SIB) in patients with breast cancer receiving adjuvant radiotherapy after breast-conserving surgery. METHODS: The eligibility criteria included unifocal breast cancer with an indication for adjuvant radiotherapy to the whole breast and boost radiotherapy to the tumor bed. The whole breast received a dose of 40 Gy and the tumor bed a total dose of 48 Gy in 16 fractions of 2.5 and 3 Gy, respectively. Radiotherapy could be given either as 3D conformal RT (3D-CRT) or as intensity-modulated radiotherapy (IMRT). The study was designed as a prospective single-arm trial to evaluate the acute toxicity of the treatment regimen. The study hypothesis was that the frequency of acute skin reaction grade ≥2 would be 20% or less. RESULTS: From November 2013 through July 2014, 149 patients were recruited from 12 participating centers. Six patients were excluded, leaving 143 patients for analysis. Eighty-four patients (58.7%) were treated with 3D-CRT and 59 (41.3%) with IMRT. Adherence to the treatment protocol was high. The rate of grade ≥2 skin toxicity was 14.7% (95% confidence interval 9.8-21.4%). The most frequent grade 3 toxicity (11%) was hot flashes. CONCLUSION: This study demonstrated low toxicity of and high treatment adherence to hypofractionated adjuvant radiotherapy with SIB in a multicenter prospective trial, although the primary hypothesis was not met.

Impact of guideline changes on adoption of hypofractionation and breast cancer patient characteristics in the randomized controlled HYPOSIB trial.

PURPOSE: Hypofractionated radiotherapy is the standard of care for adjuvant whole breast radiotherapy (RT). However, adoption has been slow. The indication for regional nodal irradiation has been expanded to include patients with 0-3 involved lymph nodes. We investigated the impact of the publication of the updated German S3 guidelines in 2017 on adoption of hypofractionation and enrollment of patients with lymph node involvement within a randomized controlled phase III trial. METHODS: In the experimental arm of the HYPOSIB trial (NCT02474641), hypofractionated RT with simultaneous integrated boost (SIB) was used. In the standard arm, RT could be given as hypofractionated RT with sequential boost (HFseq), normofractionated RT with sequential boost (NFseq), or normofractionated RT with SIB (NFSIB). The cutoff date for the updated German S3 guidelines was December 17, 2017. Temporal trends were analyzed by generalized linear regression models. Multiple logistic regression models were used to investigate the influence of time (prior to/after guideline) and setting (university hospital/other institutions) on the fractionation patterns. RESULTS: Enrollment of patients with involved lymph nodes was low throughout the trial. Adoption of HFseq increased over time and when using the guideline publication date as cutoff. Results of the multiple logistic regressions showed an interaction between time and setting. Furthermore, the use of HFseq was significantly more common in university hospitals. CONCLUSION: The use of HFseq in the standard arm increased over the course of the HYPOSIB trial and after publication of the S3 guideline update. This was primarily driven by patients treated in university hospitals. Enrolment of patients with lymph node involvement was low throughout the trial.

Hyperfractionated accelerated radiation therapy plus cetuximab plus cisplatin chemotherapy in locally advanced inoperable squamous cell carcinoma of the head and neck : Final 5­year results of a phase II study.

BACKGROUND: Cetuximab (CET) is a potent inhibitor of the epidermal growth factor receptor and has been shown to have activity in squamous cell carcinoma of the head and neck (SCCHN). We conducted a single-arm phase II trial of a combination therapy comprising cisplatin (CIS), CET and hyperfractionated accelerated radiotherapy (HART). PATIENTS AND METHODS: Patients with UICC stage III or IVA/B, M0 SCCHN were enrolled and treated with an initial dose of CET (400 mg/m2) and then with a weekly dosage of 250 mg/m2 during HART. HART was started with a prescribed dosage of 2.0 Gy per day for 3 weeks, followed by 1.4 Gy twice daily to a total dose of 70.6 Gy to the gross tumour volume. CIS (40 mg/m2) was administered weekly (days 1, 8, 15, 22, 29 and 36). The primary objective of the phase II study was to determine the 2­year progression-free survival (PFS). RESULTS: Between November 2007 and November 2010, a total of 74 patients were enrolled in the study, of whom 65 were evaluable (83% were men). Median age was 56 years (range 37-69 years). An Oropharyngeal primary tumour was diagnosed in 49%, T4a,b in 65% and N2/3 in 96% of the patients. Of these patients, 85% were smokers or ex-smokers. Complete remission (CR) was observed in 23 patients (35%). The most common toxicity grade was ≥3, including mucositis (58%) and dysphagia (52%). The 2­ and 5­year overall survival rates were 64 and 41%, the 2­ and 5­year PFS rates were 45 and 32%, and the 2­ and 5­year locoregional control rates were 47 and 33%, respectively. CONCLUSION: The combination of weekly CIS with HART plus CET is a feasible regimen for these unfavourable smoking-induced cancers. However, the parallel US study (RTOG 0522) showed no advantage of the enhanced triple therapy compared to chemoradiotherapy alone.

Analysis of bevacizumab-based preoperative radiochemotherapy in patients with locally advanced rectal cancer on surgery-associated spectrum of complications.

BACKGROUND: Preoperative radiochemotherapy (RCT) is a standard of care for patients with locally advanced rectal cancer (LARC; stages II and III). Results of our phase II study (BevXelOx-RT) have shown that this regimen is feasible but without a significant improvement of pathological complete response. Whether preoperatively administered bevacizumab, due to its specific toxicity profile, leads to increased rates of surgical complications is currently a subject for debate. This analysis focusses on the surgery-associated spectrum of complications. METHODS: Data from 62 patients with rectal cancer (uT3-4; N0/1, M0) of the phase II trial were analyzed. Patients received radiotherapy (50.4/1.8 Gy fractions), simultaneous bevacizumab 5 mg/kg (d1, d15, d29), and capecitabine 825 mg/m(2) twice daily (d1-14, d22-35), oxaliplatin 50 mg/m(2) (d1, d8, d22, d29). Four to six weeks after RCT, surgical resection was performed. RESULTS: Overall, 69/69 patients underwent surgery, and 66 (95.7 %) patients had R0 resection. Surgery was mainly conducted (in 66 %) by highly experienced surgeons (>20 resections of rectal cancer/year) with differences between the institutions due to the operative procedures but without effects on the rate of R0 resection or complications. The average duration of surgery was 239 min (±10). Frequency of multivisceral resections (11 %), intraoperative (8 %) and postoperative (43 %) complications were all in the expected range. In particular, we did not observe an increased rate of postoperative bleedings (3 %). The postoperative mortality rate was 0 %. CONCLUSIONS: Quantity and the kind of surgery-associated spectrum of complications followed by a preoperative bevacizumab-containing RCT regimen in patients with LARC were in line with comparable trials of bevacizumab-based approaches.

Hypofractionation with simultaneous integrated boost for early breast cancer: results of the German multicenter phase II trial (ARO-2010-01).

PURPOSE: To evaluate the feasibility of hypofractionation with SIB in all settings in Germany to prepare a multicenter treatment comparison. METHODS: Eligible patients had histopathologically confirmed breast cancer operated by BCS. Patients received WBI 40.0 Gy in 16 fractions of 2.5 Gy. A SIB with 0.5 Gy per fraction was administered to the tumor bed, thereby giving 48.0 Gy in 16 fractions to the boost-PTV sparing heart, LAD, lung, contralateral breast. The primary study objective was feasibility, administration of specified dose in 16 fractions within 22-29 days with adherence to certain dose constraints (heart; LAD; contralateral breast); secondary endpoints were toxicity, QoL. RESULTS: 151 patients were recruited from 7 institutions between 07/11-10/12. 10 patients met exclusion criteria prior to irradiation. All but two patients (99%) received the prescribed dose in the PTVs. Adherence to dose constraints and time limits was achieved in 89% (95% CI 82% to 93%). 11 AE were reported in 10 patients; five related to concurrent endocrine therapy. Two of the AEs were related to radiotherapy: grade 3 hot flushes in two cases. QoL remained unchanged. CONCLUSION: Hypofractionation with a SIB is feasible and was well tolerated in this study.

Hypofractionation with simultaneous integrated boost after breast-conserving surgery: Long term results of two phase-II trials.

PURPOSE: To analyze long-term results of two multicenter prospective single-arm trials (ARO-2010-01 and ARO-2013-04) investigating adjuvant hypofractionated radiotherapy (HF) with simultaneous integrated boost (SIB) after breast-conserving surgery (BCS). METHODS: Eligible patients had histopathologically confirmed unifocal breast cancer planned for whole breast irradiation plus boost radiotherapy to the tumor bed. In both studies, a total dose of 40 Gy was applied to the whole breast and of 48 Gy to the tumor bed in 16 fractions of 2.5 and 3.0 Gy. Radiotherapy could be given either as three-dimensional conformal radiotherapy (3D-CRT) or as intensity-modulated radiotherapy (IMRT). The primary study objectives were feasibility and security within an observation period of six months. The current investigation focuses on long-term efficacy and toxicities. RESULTS: Between 2011 and 2014, both trials enrolled 300 patients in total. Data from 274 of these patients could be used for the current analysis. The median follow-up time was 60 months and the 5-year disease-free survival 92.1%. Three patients suffered a local recurrence (after 36-72 months) while a regional recurrence occurred in one patient (after 17 months). The 5-year local control rate in the breast was 99.6%. 63.5% of all patients did not report any late radiation-related toxicity, 28.5% reported grade 1 and 7.3% grade 2 toxicities. The highest late toxicity was grade 3 in 2 women (0.7%, telangiectasia and lymphedema of the breast). CONCLUSION: Our analysis demonstrates favorable efficacy and low rates of long-term side effects of HF with SIB after BCS. Randomized controlled phase III trials are ongoing.

Metastases-directed Radiotherapy in Addition to Standard Systemic Therapy in Patients with Oligometastatic Breast Cancer: Study protocol for a randomized controlled multi-national and multi-center clinical trial (OLIGOMA).

BACKGROUND: Several recent randomized therapeutic exploratory trials demonstrated improvement of progression-free survival and in some even overall survival using stereotactic body radiotherapy in patients with oligometastatic disease. However, only very few patients enrolled in these trials had breast cancer, and results from confirmatory trials are lacking. METHODS/DESIGN: The OLIGOMA-trial is a randomized controlled multi-national multi-center therapeutic confirmatory trial studying the role of local ablative radiotherapy as an additive treatment in patients with oligometastatic breast cancer receiving standard systemic therapy. Patients will be randomized 1:1 to standard systemic therapy according to national guidelines with or without radiotherapy to all metastatic sites. Randomization will be stratified according to type and line of systemic therapy, which has to be determined by a multidisciplinary tumor board before enrollment. Patients with up to five metastatic lesions are eligible, including patients with up to three brain metastases (only in case of extracranial disease) and with locoregional recurrence (only in case of additional metastatic lesions). In the standard arm, palliative radiotherapy to symptomatic metastases is permitted if at least one lesion remains untreated. The co-primary endpoints are progression-free survival and quality of life. The primary hypothesis is that progression-free survival in the experimental arm will be superior to the standard arm while simultaneously demonstrating non-inferiority of quality of life at 12 weeks after randomization. Secondary endpoints are feasibility, overall survival, toxicity, quality of life and patient satisfaction. A translational sub-study with collection of ctDNA will be conducted. DISCUSSION: The OLIGOMA-trial will provide high level evidence on the use of and benefit from local ablative radiotherapy for patients with oligometastatic breast cancer. TRIAL REGISTRATION: The OLIGOMA-trial is registered at clinicialtrials.gov under the identification NCT04495309. The related information was first posted on July 31st 2020.

Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer.

PURPOSE: To evaluate the safety and activity of preoperative radiotherapy (RT) with concurrent cetuximab, capecitabine, and oxaliplatin in rectal cancer patients. PATIENTS AND METHODS: A total of 60 patients with rectal cancer (T3-T4 or N+, M1 allowed) entered the trial at five investigator sites; the data from 58 patients were assessable. Cetuximab was given as an initial dose of 400 mg/m2 7 days before the start of RT, and then at 250 mg/m2 once weekly during RT (50.4 Gy in 28 fractions). Capecitabine and oxaliplatin were administered according to an established schedule of oxaliplatin (50 mg/m2 on Days 1, 8, 22, and 29) and capecitabine (Days 1-14 and 22-35) at three dose levels: 1,000, 1,300, and 1,650 mg/m2/d during the Phase I part of the study. The main endpoint of the Phase II was the pathologic complete response rate. RESULTS: Thirteen patients were included in the Phase I part of the study, and the maximal tolerated dose was not reached. Overall, 48 patients were treated at the recommended dose of capecitabine (1,650 mg/m2) and 45 patients (94%) underwent surgery. A pathologic complete response was observed in 4 patients (9%), and moderate (n=12), minimal (n=10), and no tumor regression (n=2) was noted in 24 (53%) of 45 patients. The mean radiation dose intensity, cetuximab, capecitabine, oxaliplatin was 98%, 95%, 94%, and 94%, respectively. The incidence of Grade 3-4 diarrhea was restricted to 19%. Postoperative complications of any grade occurred in 33% of patients. CONCLUSIONS: The results of our study have shown that cetuximab can be combined safely with capecitabine and oxaliplatin plus RT. The low pathologic complete response rate achieved should stimulate additional preclinical investigations to establish the best sequence of triple combinations.

Hypo-fractionated SBRT for localized prostate cancer: a German bi-center single treatment group feasibility trial.

BACKGROUND: For prostate cancer treatment, treatment options with minimal side effects are desired. External beam radiation therapy (EBRT) is non-invasive, standard of care and delivered in either conventional fractionation over 8 weeks or with moderate hypo-fractionation over about 5 weeks. Recent advances in radiotherapy technology have made extreme hypo-fractionated stereotactic body radiation therapy (SBRT) of prostate cancer feasible, which has not yet been introduced as a standard treatment method in Germany. Initial results from other countries are promising, but long-term results are not yet available. The aim of this study is to investigate feasibility and effectiveness of SBRT for prostate cancer in Germany. METHODS/DESIGN: This German bi-center single group trial (HYPOSTAT) is designed to evaluate feasibility and effectiveness, as measured by toxicity and PSA-response, respectively, of an extreme hypo-fractionated SBRT regimen with five fractions of 7 Gy in treatment of localized low and intermediate risk prostate cancer. The target volume includes the prostate with or without the base of seminal vesicles depending on risk stratification and uncertainty margins that are kept at 3-5 mm. SBRT treatment is delivered with the robotic CyberKnife system, which was recently introduced in Germany. Acute and late toxicity after one year will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE v. 4.0), Radiation Therapy Oncology Group (RTOG) and International Prostate Symptom Score (IPSS) Scores. The quality of life will be assessed before and after treatment with the EORTC QLQ C30 questionnaire. Hypothesizing that the proportion of patients with grade 2 side effects or higher is less or equal than 2.8%, thus markedly lower than the standard EBRT percentage (17.5%), the recruitment target is 85 patients. DISCUSSION: The HYPOSTAT trial aims at demonstrating short term feasibility of extreme hypo-fractioned SBRT for the treatment of prostate cancer and might be used as the pilot study for a multi-center multi-platform or for randomized-controlled trials comparing conventional radiotherapy with SBRT for localized prostate cancer in the future. The study concept of patient enrollment, follow up and evaluation by multiple public university clinics and actual patient treatment in dedicated private radiosurgery practices with high-tech radiation equipment is unique for clinical trials. STUDY STATUS: The study is ongoing and currently recruiting patients. TRIAL REGISTRATION: Registration number: NCT02635256 ( clinicaltrials.gov ). Registered 8 December 2015.

[What do I have to do to start my clinical study?]. / Was muss ich tun, um eine klinische Studie starten zu können?

"What do I have to do to start my clinical study" is one question often asked by physicians new to the field of medical research. Even many experienced researchers are challenged by this question given the complex and rapidly changing legal and regulatory aspects of clinical studies. In this article we will offer a guide to the planning of your clinical study.

Phase II trial of preoperative radiochemotherapy with concurrent bevacizumab, capecitabine and oxaliplatin in patients with locally advanced rectal cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The prognostic value of tumor necrosis in patients undergoing stereotactic radiosurgery of brain metastases.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Preoperative chemoradiation therapy with capecitabine/oxaliplatin and cetuximab in rectal cancer: long-term results of a prospective phase 1/2 study.

PURPOSE: We have previously shown that the addition of cetuximab to chemoradiation therapy failed to improve complete response rates (pCR) in rectal cancer. Here we report the long-term results of the cetuximab added to preoperative radiation therapy with capecitabine and oxaliplatin (CET-CAPOX-RT) phase 1/2 study that evaluated preoperative chemoradiation with cetuximab, capecitabine, and oxaliplatin in patients with rectal cancer. METHODS AND MATERIALS: The median follow-up was 63 months (range, 5-73 months). Sixty patients were enrolled; 3 patients were excluded due to protocol violation, and 4 died before surgery. Total mesorectal excision was performed in 53 patients, in 85% (n=45) with curative intention (M0-status). Secondary end points including overall survival (OS) disease-free survival (DFS) and cancer-specific survival (CSS) were calculated. The prognostic value of KRAS mutation status was also assessed. RESULTS: Histopathological examination confirmed ypUICC stages 0 (n=4; pCR), I (n=17), II (n=10), III (n=14), and IV (n=8). For patients who underwent surgery (n=53), OS at 1, 3, and 5 years was 88.7%, 83%, and 75.5%, respectively, whereas CSS rates were 94.1%, 88.1%, and 78.1%, respectively. In the 45 patients who were treated with curative intent (M0), the OS rates at 1, 3, and 5 years were 91.1%, 88.9%, and 86.7%, respectively; whereas CSS rates were 97.6%, 95.2%, and 90.3%, respectively; and DFS rates were 90.7%, 88.3%, and 88.3%, respectively. We did not find any locoregional failure in patients with M0-status (n=45). Chronic toxicity was rare. KRAS mutations, as detected in 33.3%, showed no correlation with the clinicopathological parameters nor significance for either OS (P=.112), CSS (P=.264), or DFS (P=.565). CONCLUSIONS: Taken together, chemoradiation therapy combined with cetuximab is safe, feasible, and offers excellent survival rates. KRAS mutation status was not a predictive factor. Importantly, lack of improvement in pCR rate did not translate to poor survival in our clinical trial.

Concurrent chemoradiation of metastases with capecitabine and oxaliplatin and 3D-CRT in patients with oligometastatic colorectal cancer: results of a phase I study.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Does Radiotherapy Have Curative Potential in Metastatic Patients? The Concept of Local Therapy in Oligometastatic Breast Cancer.

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.

Margins! Margins. Margins? How Important Is Margin Status in Breast-Preserving Therapy?

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.

Biomarkers for cetuximab-based neoadjuvant radiochemotherapy in locally advanced rectal cancer.

PURPOSE: Phase II trials in locally advanced rectal cancer have shown that cetuximab-based neoadjuvant radiochemotherapy is feasible but without an improvement in complete pathologic response rates. Our goal was to identify patients who would benefit from cetuximab-based neoadjuvant chemoradiation measuring gene expression levels of proteins involved in tumor growth [endothelial growth factor receptor (EGFR)], angiogenesis [VEGF, VEGF receptors 1 and 2 (VEGFR1, VEGFR2)], DNA repair [excision repair cross-complementing 1 (ERCC1)], and drug metabolism [thymidylate synthetase (TS)]. We also determined mutation status of KRAS and BRAF. EXPERIMENTAL DESIGN: This study was carried out on 130 patients with locally advanced rectal cancer who were enrolled in 4 different phase II clinical trials, using cetuximab-based chemoradiation. Tumor tissues were obtained before neoadjuvant and at surgical therapy. After microdissection, intratumoral gene expression levels and KRAS/BRAF mutation status were analyzed. RESULTS: A significant decrease of TS, VEGFR1, and VEGFR2 gene expression was seen following neoadjuvant therapy (P < 0.03). High pretreatment VEGF gene expression levels were associated with nonresponse (P = 0.070). KRAS mutations were found in 42% and mutant KRAS (KRAS mt) was significantly associated with pathologic nonresponse (P = 0.037). In patients with wild-type KRAS (KRAS wt), low EGFR was significantly associated with higher nonresponse and VEGF mRNA expressions were associated with complete pathologic response (P = 0.012; P = 0.06). KRAS transversion (KRAS tv) was associated with tumor regression: nonresponse was more common in patients with KRAS tv than with KRAS wt (P = 0.007). BRAF V600E mutations were not detected in any of the patients. CONCLUSION: This study suggests that pretreatment intratumoral EGFR and VEGF mRNA expression levels as well as KRAS mutation status are predictive markers of pathologic response to neoadjuvant cetuximab-based chemoradiation in locally advanced rectal cancer.

EGF61 polymorphism predicts complete pathologic response to cetuximab-based chemoradiation independent of KRAS status in locally advanced rectal cancer patients.

BACKGROUND: Cetuximab has shown 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 epidermal growth factor receptor pathway, angiogenesis, antibody-dependent cell-mediated cytotoxicity, 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. METHODS: 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 done by 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 III vs. grade IV: complete response). RESULTS: Patients with the epidermal growth factor (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. CONCLUSION: This study suggested 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.

Preoperative radiotherapy of advanced rectal cancer with capecitabine and oxaliplatin with or without cetuximab: A pooled analysis of three prospective phase I-II trials.

PURPOSE: A pooled analysis of three prospective trials of preoperative radiochemotherapy (RCT) for rectal cancer by using oxaliplatin and capecitabine with or without cetuximab was performed to evaluate the impact of additional cetuximab on pathologic complete response (pCR) rates and tumor regression (TRG) grades. METHODS AND MATERIALS: Of 202 patients, 172 patients met the inclusion criteria (primary tumor stage II/III, M0). All patients received concurrent RCT, and 46 patients received additional cetuximab therapy. A correlation of pretreatment clinicopathologic factors and cetuximab treatment with early pCR rates (TRG > 50%) was performed with univariate and multivariate analyses. Toxicity data were recorded for all patients. RESULTS: Of 172 patients, 24 (14%) patients achieved a pCR, and 84 of 172 (71%) patients showed a TRG of >50% in the surgical specimen assessment after preoperative treatment. Age, gender, and T/N stages, as well as localization of the tumor, were not associated with pCR or good TRG. The pCR rate was 16% after preoperative RCT alone and 9% with concurrent cetuximab therapy (p = 0.32). A significantly reduced TRG of >50% was found after RCT with cetuximab compared to RCT alone (p = 0.0035). This was validated by a multivariate analysis with all available clinical factors (p = 0.0037). Acute toxicity and surgical complications were not increased with additional cetuximab. CONCLUSIONS: Triple therapy with RCT and cetuximab seems to be feasible, with no unexpected toxicity. Early response assessment (TRG), however, suggests subadditive interaction. A longer follow-up (and finally randomized trials) is needed to draw any firm conclusions with respect to local and distant failure rates.