Radiation Oncology

Boström, Jan; Hadizadeh, Dariusch R; Block, Wolfgang; Willinek, Winfried; Schild, Hans H; Träber, Frank

2013 Radiation Oncology

doi: 10.1186/1748-717x-8-54pmid: 23497623

Abstract Background The incidence of radionecrosis after radiosurgery is 5–20%. That radionecrosis after radiosurgery may be confused with a malignant tumor is a known phenomenon and problem. Methods Three similarly treated patients with cAVM, 1 patient with symptomatic radionecrosis and 2 patients with normal post-radiation MRI changes, were selected and studied in detail with magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance spectroscopy (MRS). 2 cAVM were located in eloquent locations and were classified as Spetzler-Martin grade (SM) III such that interdisciplinary radiosurgery was recommended; a third patient with a left frontal SM II cAVM refused surgery. 1 patient was male, and 2 were female. The patient’s ages ranged from 38 to 62 years (median, 39 years). The nidus volume (= planning target volume = PTV) ranged from 2.75 to 6.89 ccm (median, 6.41 ccm). The single dose was 20 Gy at the isocenter of the PTV encompassing the 80 – 90% isodose. The median follow-up period was 20 months (range, 16 – 84 months). Toxicities were evaluated with the Common Terminology Criteria (CTC) for adverse events version 3.0. Results No patient suffered a bleeding from cAVM during the study period. A complete nidus occlusion was shown in all patients with time-resolved MRA. All patients showed radiogenic MRI changes, 1 patient showed excessive radionecrosis. This patient was oligosymptomatic and under temporary corticoid therapy symptoms resolved completely. Following patterns associated with radionecrosis in the MRS studies were identified in our collective: • 2D spectroscopic imaging (2D-SI) revealed much lower concentrations of metabolites in the lesion as compared to contralateral healthy tissue in all patients. • Whereas regions with regular post-radiosurgery effects showed almost normal levels of Cho and a Cho/Cr ratio < 2.0, regions with radionecrosis were characterized by increased lipid levels and a Cho/Cr ratio > 2.0 in conjunction with decreased absolute levels of all metabolites, especially of Cr and NAA. Conclusions MRS is an increasingly valuable tool for the differential diagnosis of radiation reactions. Specific patterns of MRS spectra in radionecrosis were identified; in synopsis with clinical parameters, these changes have to be taken into account to avoid misdiagnosis.

Siva, Shankar;Pham, Daniel;Gill, Suki;Bressel, Mathias;Dang, Kim;Devereux, Thomas;Kron, Tomas;Foroudi, Farshad

2013 Radiation Oncology

doi: 10.1186/1748-717X-8-248pmid: 24160868

Abstract Background and purpose Stereotactic ablative body radiotherapy (SABR) is an emerging treatment modality for primary renal cell carcinoma. To account for respiratory-induced target motion, an internal target volume (ITV) concept is often used in treatment planning of SABR. The purpose of this study is to assess patterns of kidney motion and investigate potential surrogates of kidney displacement with the view of ITV verification during treatment. Material and methods Datasets from 71 consecutive patients with free breathing four-dimensional computed tomography (4DCT) planning scans were included in this study. The displacement of the left and right hemi-diaphragm, liver dome and abdominal wall were measured and tested for correlation with the displacement of the both kidneys and patient breathing frequency. Results Nine patients were excluded due to severe banding artifact. Of 62 evaluable patients, the median age was 68 years, with 41 male patients and 21 female patients. The mean (range) of the maximum, minimum and average breathing frequency throughout the 4DCTs were 20.1 (11–38), 15.1 (9–24) and 17.3 (9–27.5) breaths per minute, respectively. The mean (interquartile range) displacement of the left and right kidneys was 0.74 cm (0.45-0.98 cm) and 0.75 cm (0.49-0.97) respectively. The amplitude of liver-dome motion was correlated with right kidney displacement (r=0.52, p<0.001), but not with left kidney displacement (p=0.796). There was a statistically significant correlation between the magnitude of right kidney displacement and that of abdominal displacement (r=0.36, p=0.004), but not the left kidney (r=0.24, p=0.056). Hemi-diaphragm displacements were correlated with kidney displacements respectively, with a weaker correlation for the left kidney/left diaphragm (r= 0.45, [95% CI 0.22 to 0.63], p=<0.001) than for the right kidney/right diaphragm (r=0.57, [95% CI 0.37 to 0.72], p=<0.001). Conclusions For the majority of patients, maximal left and right kidney displacement is subcentimeter in magnitude. The magnitude of kidney motion cannot be reliably estimated from the diaphragmatic, liver dome or abdominal wall surrogates. One explanation may be that the kidneys are not uniformly in contact with the surrogates investigated in this study. Further investigation is required before surrogates of kidney displacement are used for clinical SABR delivery.

Lee, Sung Uk;Kim, Dae Yong;Kim, Sun Young;Baek, Ji Yeon;Chang, Hee Jin;Kim, Min Ju;Kim, Tae Hyun;Park, Ji Won;Oh, Jae Hwan

2013 Radiation Oncology

doi: 10.1186/1748-717X-8-258pmid: 24188746

Abstract Background To compare the short-term tumor response and long-term clinical outcome of two preoperative chemoradiotherapy (CRT) regimens for locally advanced rectal cancer. Methods This study included 231 patients scheduled for preoperative CRT using two chemotherapeutic protocols from April 2003–August 2006. Pelvic radiotherapy (50.4 Gy) was delivered concurrently with capecitabine (n = 148) or capecitabine/irinotecan (n = 83). Surgery was performed 4–8 weeks after CRT completion. Tumor responses to CRT were assessed using both radiologic and pathologic measurements. Radiologic responses were evaluated by magnetic resonance volumetry, which was performed at the initial work-up and after completion of preoperative CRT just before surgery. Pathologic responses were assessed with downstaging (ypStage 0-1) and grading tumor regression. Clinical outcomes were evaluated in terms of local control, relapse-free survival, and overall survival rates. Results Radiologic examination demonstrated that tumor volume decreased by 65.6% in the capecitabine group and 66.8% capecitabine/irinotecan group (p = 0.731). Postoperative pathologic stage determination showed that tumor downstaging occurred in 44.1% of the capecitabine group and 48.6% of the capecitabine/irinotecan group (p = 0.538). The sum of tumor regression grade 3 (near complete response) and 4 (complete response) after CRT were 28.6% in the capecitabine group and 37.5% in the capecitabine/irinotecan group (p = 0.247). There were no significant differences between the two groups in 5-year local control (91.7% vs. 92.5%; p = 0.875), relapse-free survival (80.8% vs. 77.2%; p = 0.685), and overall survival (88.4% vs. 90.4%; p = 0.723). Conclusions This study revealed no differences in the short-term tumor response and long-term clinical outcome between preoperative capecitabine and capecitabine/irinotecan CRT regimens for locally advanced rectal cancer.

Summerer, Isolde;Niyazi, Maximilian;Unger, Kristian;Pitea, Adriana;Zangen, Verena;Hess, Julia;Atkinson, Michael J;Belka, Claus;Moertl, Simone;Zitzelsberger, Horst

2013 Radiation Oncology

doi: 10.1186/1748-717X-8-296pmid: 24373621

Abstract Introduction Circulating microRNAs (miRNAs) are easily accessible and have already proven to be useful as prognostic markers in cancer patients. However, their origin and function in the circulation is still under discussion. In the present study we analyzed changes in the miRNAs in blood plasma of head and neck squamous cell carcinoma (HNSCC) patients in response to radiochemotherapy and compared them to the changes in a cell culture model of primary HNSCC cells undergoing simulated anti-cancer therapy. Materials and methods MiRNA-profiles were analyzed by qRT-PCR arrays in paired blood plasma samples of HNSCC patients before therapy and after two days of treatment. Candidate miRNAs were validated by single qRT-PCR assays. An in vitro radiochemotherapy model using primary HNSCC cell cultures was established to test the possible tumor origin of the circulating miRNAs. Microarray analysis was performed on primary HNSCC cell cultures followed by validation of deregulated miRNAs via qRT-PCR. Results Unsupervised clustering of the expression profiles using the six most regulated miRNAs (miR-425-5p, miR-21-5p, miR-106b-5p, miR-590-5p, miR-574-3p, miR-885-3p) significantly (p = 0.012) separated plasma samples collected prior to treatment from plasma samples collected after two days of radiochemotherapy. MiRNA profiling of primary HNSCC cell cultures treated in vitro with radiochemotherapy revealed differentially expressed miRNAs that were also observed to be therapy-responsive in blood plasma of the patients (miR-425-5p, miR-21-5p, miR-106b-5p, miR-93-5p) and are therefore likely to stem from the tumor. Of these candidate marker miRNAs we were able to validate by qRT-PCR a deregulation of eight plasma miRNAs as well as miR-425-5p and miR-93-5p in primary HNSCC cultures after radiochemotherapy. Conclusion Changes in the abundance of circulating miRNAs during radiochemotherapy reflect the therapy response of primary HNSCC cells after an in vitro treatment. Therefore, the responsive miRNAs (miR-425-5p, miR-93-5p) may represent novel biomarkers for therapy monitoring. The prognostic value of this exciting observation requires confirmation using an independent patient cohort that includes clinical follow-up data.

Tamaki, Tomoaki; Ohno, Tatsuya; Kiyohara, Hiroki; Noda, Shin-ei; Ohkubo, Yu; Ando, Ken; Wakatsuki, Masaru; Kato, Shingo; Kamada, Tadashi; Nakano, Takashi

2013 Radiation Oncology

doi: 10.1186/1748-717x-8-79pmid: 23561250

Abstract Recurrences of cervical cancer after definitive radiotherapy often occur at common iliac or para-aortic lymph nodes as marginal lymph node recurrences. Patients with these recurrences have a chance of long-term survival by optimal re-treatment with radiotherapy. However, the re-irradiation often overlaps the initial and the secondary radiotherapy fields and can result in increased normal tissue toxicities in the bowels or the stomach. Carbon-ion radiotherapy, a form of particle beam radiotherapy using accelerated carbon ions, offers more conformal and sharp dose distribution than X-ray radiotherapy. Therefore, this approach enables the delivery of high radiation doses to the target while sparing its surrounding normal tissues. Marginal lymph node recurrences in common iliac lymph nodes after radiotherapy were treated successfully by carbon-ion radiotherapy in two patients. These two patients were initially treated with a combination of external beam radiotherapy and intracavitary and interstitial brachytherapy. However, the diseases recurred in the lymph nodes near the border of the initial radiotherapy fields after 22 months and 23 months. Because re-irradiation with X-ray radiotherapy may deliver high doses to a section of the bowels, carbon-ion radiotherapy was selected to treat the lymph node recurrences. A total dose of 48 Gy (RBE) in 12 fractions over 3 weeks was given to the lymph node recurrences, and the tumors disappeared completely with no severe acute toxicities. The two patients showed no evidence of disease for 75 months and 63 months after the initial radiotherapy and for 50 months and 37 months after the carbon-ion radiotherapy, respectively. No severe late adverse effects are observed in these patients. The two presented cases suggest that the highly conformal dose distribution of carbon-ion radiotherapy may be beneficial in the treatment of marginal lymph node recurrences after radiotherapy. In addition, the higher biological effect of carbon-ion radiotherapy and its superior dose distribution may provide more effective tumor control in treatment for re-irradiation of the marginal recurrences in radiation resistant tumors other than cervical cancer.

Kim, Young-Il;Park, Joong-Won;Kim, Bo Hyun;Woo, Sang Myung;Kim, Tae Hyun;Koh, Young Hwan;Lee, Woo Jin;Kim, Chang-Min

2013 Radiation Oncology

doi: 10.1186/1748-717X-8-292pmid: 24359879

Abstract Background A standard treatment for unresectable advanced-stage intrahepatic cholangiocarcinoma (IHCC) has not yet been established. Although neoadjuvant concurrent chemoradiotherapy (CCRT) and liver transplantation are associated with long-term survival in select patients, the outcomes of CCRT for advanced-stage unresectable IHCC remain unclear. The aim of our study was to evaluate the outcomes of CCRT in patients with unresectable advanced-stage IHCC. Methods We retrospectively reviewed the records of all patients with unresectable advanced stage (stage IVa or IVb) IHCC who were pathologically diagnosed and treated at National Cancer Center, Korea, from June 2001 to March 2012. Of the total of 92 patients, 25 (27.1%) received capecitabine plus cisplatin (XP) chemotherapy with external radiotherapy (RT) (XP-CCRT group) and 67 (72.8%) received XP chemotherapy alone (XP group). The clinical characteristics and outcomes of the 2 groups were compared. Results The 92 patients comprised 72 male and 20 female patients, with a median age of 58 years (range 26–78 years). The baseline clinical characteristics of the 2 groups were similar. Patients in the XP-CCRT group received a mean 44.7 Gy of RT and a mean 5.6 cycles of XP chemotherapy, whereas patients in the XP group received a mean 4.0 cycles. The disease control rate was higher in the XP-CCRT group than in the XP group, but the difference was not statistically significant (56.0% vs. 41.5%, p = 0.217). Although neutropenia was significantly more frequent in the XP-CCRT than in the XP group (48% vs. 9%, p < 0.001), the rates of other toxicities and > grade 3 toxicities did not differ. At a median follow-up of 5.3 months, PFS (4.3 vs. 1.9 months, p = 0.001) and OS (9.3 vs. 6.2 months, p = 0.048) were significantly longer in the XP-CCRT than in the XP group. Conclusions XP-CCRT was well tolerated and was associated with longer PFS and OS than XP chemotherapy alone in patients with unresectable advanced IHCC. Controlled randomized trials are required to determine whether XP-CCRT is a primary treatment option for patients with unresectable advanced IHCC.

Brooks, Frank J;Grigsby, Perry W

2013 Radiation Oncology

doi: 10.1186/1748-717X-8-294pmid: 24365202

Abstract Translational relevance Many types of cancer are located and assessed via positron emission tomography (PET) using the 18F-fluorodeoxyglucose (FDG) radiotracer of glucose uptake. There is rapidly increasing interest in exploiting the intra-tumor heterogeneity observed in these FDG-PET images as an indicator of disease outcome. If this image heterogeneity is of genuine prognostic value, then it either correlates to known prognostic factors, such as tumor stage, or it indicates some as yet unknown tumor quality. Therefore, the first step in demonstrating the clinical usefulness of image heterogeneity is to explore the dependence of image heterogeneity metrics upon established prognostic indicators and other clinically interesting factors. If it is shown that image heterogeneity is merely a surrogate for other important tumor properties or variations in patient populations, then the theoretical value of quantified biological heterogeneity may not yet translate into the clinic given current imaging technology. Purpose We explore the relation between pelvic lymph node status at diagnosis and the visually evident uptake heterogeneity often observed in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) images of cervical carcinomas. Experimental design We retrospectively studied the FDG-PET images of 47 node negative and 38 node positive patients, each having FIGO stage IIb tumors with squamous cell histology. Imaged tumors were segmented using 40% of the maximum tumor uptake as the tumor-defining threshold and then converted into sets of three-dimensional coordinates. We employed the sphericity, extent, Shannon entropy (S) and the accrued deviation from smoothest gradients (ζ) as image heterogeneity metrics. We analyze these metrics within tumor volume strata via: the Kolmogorov-Smirnov test, principal component analysis and contingency tables. Results We found no statistically significant difference between the positive and negative lymph node groups for any one metric or plausible combinations thereof. Additionally, we observed that S is strongly dependent upon tumor volume and that ζ moderately correlates with mean FDG uptake. Conclusions FDG uptake heterogeneity did not indicate patients with differing prognoses. Apparent heterogeneity differences between clinical groups may be an artifact arising from either the dependence of some image metrics upon other factors such as tumor volume or upon the underlying variations in the patient populations compared.

Tesei, Anna;Sarnelli, Anna;Arienti, Chiara;Menghi, Enrico;Medri, Laura;Gabucci, Elisa;Pignatta, Sara;Falconi, Mirella;Silvestrini, Rosella;Zoli, Wainer;D’Errico, Vincenzo;Romeo, Antonino;Parisi, Elisabetta;Polico, Rolando

2013 Radiation Oncology

doi: 10.1186/1748-717X-8-257pmid: 24180359

Abstract Background Although two-dimensional (2-D) monolayer cell cultures provide important information on basic tumor biology and radiobiology, they are not representative of the complexity of three-dimensional (3-D) solid tumors. In particular, new models reproducing clinical conditions as closely as possible are needed for radiobiological studies to provide information that can be translated from bench to bedside. Methods We developed a novel system for the irradiation, under sterile conditions, of 3-D tumor spheroids, the in vitro model considered as a bridge between the complex architectural organization of in vivo tumors and the very simple one of in vitro monolayer cell cultures. The system exploits the same equipment as that used for patient treatments, without the need for dedicated and highly expensive instruments. To mimic the passage of radiation beams through human tissues before they reach the target tumor mass, 96-multiwell plates containing the multicellular tumor spheroids (MCTS) are inserted into a custom-built phantom made of plexiglass, the material most similar to water, the main component of human tissue. Results The system was used to irradiate CAEP- and A549-derived MCTS, pre-treated or not with 20 μM cisplatin, with a dose of 20 Gy delivered in one session. We also tested the same treatment schemes on monolayer CAEP and A549 cells. Our preliminary results indicated a significant increment in radiotoxicity 20 days after the end of irradiation in the CAEP spheroids pre-treated with cisplatin compared to those treated with cisplatin or irradiation alone. Conversely, the effect of the radio- chemotherapy combination in A549-derived MCTS was similar to that induced by cisplatin or irradiation alone. Finally, the 20 Gy dose did not affect cell survival in monolayer CAEP and A549 cells, whereas cisplatin or cisplatin plus radiation caused 100% cell death, regardless of the type of cell line used. Conclusions We set up a system for the irradiation, under sterile conditions, of tumor cells grown in 3-D which allows for the use of the same dose intensities and schedules utilized in clinical practice. This irradiation system, coupled with 3-D cell cultures, has the potential to generate information that could be used to individually tailor radiotherapy.

Di Franco, Rossella; Sammarco, Elena; Calvanese, Maria Grazia; De Natale, Flora; Falivene, Sara; DiLecce, Ada; Giugliano, Francesca Maria; Murino, Paola; Manzo, Roberto; Cappabianca, Salvatore; Muto, Paolo; Ravo, Vincenzo

2013 Radiation Oncology

doi: 10.1186/1748-717x-8-57pmid: 23497676

Abstract Background and purpose The purpose of this study was to add, to the objective evaluation, an instrumental assessment of the skin damage induced by radiation therapy. Materials and methods A group of 100 patients affected by breast cancer was recruited in the study over one year. Patients were divided into five groups of 20 patients. For each group it was prescribed a different topical treatment. The following products were used: Betaglucan, sodium hyaluronate (Neoviderm®), Vitis vinifera A. s-I-M.t-O.dij (Ixoderm®), Alga Atlantica plus Ethylbisiminomethylguaicolo and Manganese Cloruro (Radioskin1®) and Metal Esculetina plus Ginko Biloba and Aloe vera (Radioskin 2®); Natural triglycerides-fitosterols (Xderit®); Selectiose plus thermal water of Avene (Trixera+®). All hydrating creams were applied twice a day starting 15 days before and one month after treatment with radiations. Before and during treatment patients underwent weekly skin assessments and corneometry to evaluate the symptoms related to skin toxicity and state of hydration. Evaluation of acute cutaneous toxicity was defined according to the RTOG scale. Results All patients completed radiotherapy; 72% of patients presented a G1 cutaneous toxicity, 18% developed a G2 cutaneous toxicity, 10% developed a G3 toxicity, no one presented G4 toxicity. The corneometry study confirmed the protective role of effective creams used in radiation therapy of breast cancer and showed its usefulness to identify radiation-induced dermatitis in a very early stage. Conclusions The preventive use of topic products reduces the incidence of skin side effects in patients treated with radiotherapy for breast cancer. An instrumental evaluation of skin hydration can help the radiation oncologist to use strategies that prevent the onset of toxicity of high degree. All moisturizing creams used in this study were equally valid in the treatment of skin damage induced by radiotherapy.

Welzel, Grit; Boch, Angela; Sperk, Elena; Hofmann, Frank; Kraus-Tiefenbacher, Uta; Gerhardt, Axel; Suetterlin, Marc; Wenz, Frederik

2013 Radiation Oncology

doi: 10.1186/1748-717x-8-9pmid: 23294485

Abstract Background Intraoperative radiotherapy (IORT) is a new treatment approach for early stage breast cancer. This study reports on the effects of IORT on radiation-related quality of life (QoL) parameters. Methods Two hundred and thirty women with stage I-III breast cancer (age, 31 to 84 years) were entered into the study. A single-center subgroup of 87 women from the two arms of the randomized phase III trial TARGIT-A (TARG eted I ntra-operative radioT herapy versus whole breast radiotherapy for breast cancer) was analyzed. Furthermore, results were compared to non-randomized control groups: n = 90 receiving IORT as a tumor bed boost followed by external beam whole breast radiotherapy (EBRT) outside of TARGIT-A (IORT-boost), and n = 53 treated with EBRT followed by an external-beam boost (EBRT-boost). QoL was collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 (QLQ-C30) and BR23 (QLQ-BR23). The mean follow-up period in the TARGIT-A groups was 32 versus 39 months in the non-randomized control groups. Results Patients receiving IORT alone reported less general pain (21.3 points), breast (7.0 points) and arm (15.1 points) symptoms, and better role functioning (78.7 points) as patients receiving EBRT (40.9; 19.0; 32.8; and 60.5 points, respectively, P < 0.01). Patients receiving IORT alone also had fewer breast symptoms than TARGIT-A patients receiving IORT followed by EBRT for high risk features on final pathology (IORT-EBRT; 7.0 versus 29.7 points, P < 0.01). There were no significant differences between TARGIT-A patients receiving IORT-EBRT compared to non-randomized IORT-boost or EBRT-boost patients and patients receiving EBRT without a boost. Conclusions In the randomized setting, important radiation-related QoL parameters after IORT were superior to EBRT. Non-randomized comparisons showed equivalent parameters in the IORT-EBRT group and the control groups.