Radiation therapy of breast cancer in the Nahe Breast Center: first results of an analysis in the context of health services research.

BACKGROUND: The first evaluation of radiotherapy results in patients with breast cancer treated as part of a multimodal oncologic therapy in the Nahe Breast Center is presented. Analysis of the results was performed using an in-practice registry. PATIENTS AND METHODS: From September 2016 to December 2017, 138 patients (median age 62.5 years; range 36-94 years) with breast cancer (right side, n = 67; left side, n = 71) received adjuvant radiation therapy. Of these, 103 patients received gyneco-oncologic care at the Nahe Breast Center, and 35 were referred from outside breast centers. The distribution into stages was as follows: stage I, n = 48; stage II, n = 68; stage III, n = 19; stage IV, n = 3. Neoadjuvant chemotherapy was given to 19 and adjuvant chemotherapy to 50 patients. Endocrine treatment was given to 120 patients. Both 3D conformal (n = 103) and intensity-modulated (n = 35) radiotherapy were performed with a modern linear accelerator. RESULTS: With a median follow-up of 60 months (1-67), local recurrence occurred in 4/138 (2.9%) and distant metastasis in 8/138 (5.8%) patients; 7/138 (5.1%) patients died of their tumors during the follow-up period. The actuarial 5­year local recurrence-free survival of all patients was 97.1%, and the actuarial 5­year overall survival of all patients was 94.9%. We observed no grade 3 or 4 radiogenic side effects. CONCLUSION: The results of radiotherapy for breast carcinoma at the Nahe Breast Center are comparable to published national and international results. In particular, the local recurrence rates in our study, determined absolutely and actuarially, are excellent, and demonstrate the usefulness of radiotherapy.

Radiotherapy for calcaneodynia, achillodynia, painful gonarthrosis, bursitis trochanterica, and painful shoulder syndrome - Early and late results of a prospective clinical quality assessment.

BACKGROUND: The aim of this prospective clinical quality assessment was to evaluate the short-term and long-term efficacy of low dose radiotherapy (RT) for calcaneodynia, achillodynia, painful gonarthrosis, painful bursitis trochanterica, and painful shoulder syndrome. METHODS: Between October 2011 and October 2013, patients with calcaneodynia, achillodynia, painful gonarthrosis, painful bursitis trochanterica, and painful shoulder syndrome were recruited for this prospective clinical quality assessment. Single doses of 0.5-1.0 Gy and a total dose of 6.0 Gy per series were used. Pain was measured before and directly after RT (early response) with a visual analogue scale (VAS). Additionally, pain relief was measured with the four-scale pain score according to "von Pannewitz" (VPS) immediately at the end of RT and during follow-up. Within this context we defined a good response as complete pain relief and markedly improved. The assessment of the long-term efficacy was carried out by a telephone survey. RESULTS: 703 evaluable patients (461 female, 242 male) with a mean age of 63.2 years (28-96) were recruited for this prospective clinical quality assessment. In 254 patients RT was performed with the linear accelerator, 449 patients received orthovoltage radiotherapy. After a median follow-up of 33 months (3-60) 437 patients could be reached for evaluation of follow up results. The mean VAS value before treatment was 6.63 (1.9-10) and immediately on completion of RT 4.51 (0-10) (p < 0,001). Concerning the VPS immediately on completion of RT, a good response could be achieved in 264/703 patients (37.6%), and with the follow up in 255/437 patients (58.4%) (p < 0.001). Only in patients with gonarthrosis we could not observe a significantly improved long-term success in comparison to the results immediately after RT (30.2% versus 29.9%). CONCLUSION: Low dose RT is a very effective treatment for the management of calcaneodynia, achillodynia, painful gonarthrosis, painful bursitis trochanterica, and painful shoulder syndrome. Due to the delayed onset of analgesic effects low dose RT results in a significantly improved long-term efficacy in comparison to the results immediately after RT particularly in patients with calcaneodynia, achillodynia, bursitis trochanterica, and shoulder syndrome.

Effect of Whole-abdominal Irradiation on Penetration Depth of Doxorubicin in Normal Tissue After Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in a Post-mortem Swine Model.

BACKGROUND: This study was performed to evaluate the impact of whole-abdominal irradiation on local penetration of doxorubicin into the peritoneum and the abdominal organs in a post-mortem swine model. MATERIALS AND METHODS: Doxorubicin was aerosolized into the abdominal cavity of swine at a pressure of 12 mmHg CO2 at room temperature (25°). One swine was subjected to pressurized intraperitoneal aerosol chemotherapy (PIPAC) using Micropump© without irradiation; the second one received 2 Gy and the third one 7 Gy whole-abdominal irradiation, 15 min prior to PIPAC application. Samples of the peritoneal surface were extracted at different positions from within the abdominal cavity. In-tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. RESULTS: The depth of penetration of doxorubicin was found to be wide-ranging, between 17 µm on the surface of the stomach and 348 µm in the small intestine. The penetration depth into the small intestine was 348 µm, 312 µm and 265 µm for PIPAC alone, PIPAC with 2 Gy irradiation and PIPAC with 7 Gy irradiation, respectively (p<0.05). The penetration into the liver was 64 µm, 55 µm and 40 µm, respectively (p=0.05). CONCLUSION: Irradiation was not found to increase the depth of doxorubicin penetration into normal tissue in the post-mortem swine model. A reduction of doxorubicin penetration was observed after application of higher irradiation doses. Further studies are warranted to determine if irradiation can be used safely as chemopotentiating agent for patients with peritoneal metastases treated with PIPAC.

Low-Dose Radiation Therapy for Benign Painful Skeletal Disorders: The Typical Treatment for the Elderly Patient?

PURPOSE: To prospectively evaluate the short-term and long-term efficacy of low-dose radiation therapy (RT) for calcaneodynia, achillodynia, painful gonarthrosis, and painful bursitis trochanterica in elderly patients aged ≥70 years. METHODS AND MATERIALS: Between October 2011 and October 2013, patients aged ≥70 years with painful degenerative disorders of joints were recruited for a prospective trial. Single doses of 0.5 to 1.0 Gy and a total dose of 6.0 Gy per series were used. Pain was measured before and right after RT (early response) with a 10-point visual analogue scale. Additionally, pain relief was measured with the 4-point pain scale according to "von Pannewitz" immediately on completion of RT and during follow-up. We defined a good response as complete pain relief and markedly improved. RESULTS: A total of 166 evaluable patients with a mean age of 76.6 years (range, 70-90 years) with calcaneodynia (n=51), achillodynia (n=8), painful gonarthrosis (n=80), and painful bursitis trochanterica (n=27) were recruited. The mean visual analogue scale value before treatment was 6.38 and immediately upon completion of RT was 4.49 (P<.001). Concerning the von Pannewitz status immediately on completion of RT, 6 patients were free of pain, 56 were much improved, 47 reported slight improvement, and 57 experienced no change. After a median follow-up of 29 months, 109 patients could be reached for evaluation of follow-up results. Thirty-three patients were free of pain, 21 had marked improvement, 18 had some improvement, and 37 experienced no change. Therefore, a good response immediately on completion of RT could be achieved in 62 of 166 patients, and with the follow-up in 54 of 109 patients (P=.001). CONCLUSIONS: Low-dose RT is a very effective treatment for the management of painful degenerative disorders of joints in the elderly. Low-dose RT offers a low-risk, genuinely conservative, noninvasive therapeutic alternative for elderly patients.

Zoledronic Acid Inhibits the Motility of Cancer Stem-like Cells from the Human Breast Cancer Cell Line MDA-MB 231.

BACKGROUND/AIM: Various effects on tumor cells have been described for zoledronic acid (ZOL). However, only limited data exist regarding its influence on the motility of tumor cells. Since migration of tumor stem cells is a decisive step in metastasis, we examined whether ZOL reduces their motility. MATERIALS AND METHODS: We investigated the effects of ZOL on stem-like progenitor cells obtained via the formation of spheroids from the human breast cancer cell line MDA-MB 231. Stem cell properties were verified by measurement of high CD44 expression and absence of CD24 expression. Motility was explored by time-resolved videography, protein expression by western blotting. RESULTS: ZOL strongly reduced the migration of stem-like progenitor cells. Cellular velocity was reduced by 61% following exposure to 1 µM ZOL and by 82% after exposure to 10 µM ZOL. Accumulated distance traveled by the cells was reduced by 60% and 79% after exposure to 1 µM and 10 µM ZOL, respectively. The remaining cellular motility led to very little change in distance, with cellular activity appearing more as "stepping on the spot". The reduced motility might be due to reduced phosphorylation of focal adhesion kinase (FAK), an important enzyme in cellular migration. CONCLUSION: ZOL reduces the motility and cellular velocity of breast cancer cells in vitro. The reduced mobility might slow down or even stop metastasis, which is a known result of adjuvant ZOL therapy in breast cancer patients. In vivo studies are warranted to evaluate the impact of the reduced motility on the metastatic cascade.

Extracranial oral cavity metastasis from glioblastoma multiforme: A case report.

Glioblastoma multiforme is the most common primary malignant brain tumor. The clinical outcome following diagnosis remains extremely poor. The treatment of choice is wide surgical resection of the visible tumor, frequently followed by adjuvant combined radiochemotherapy (RCTx) with temozolomide as the chemotherapeutic agent. Extracranial metastases are extremely rare, with <200 cases of extracranial metastases from glioblastoma multiforme reported in the literature to date. We herein present a case of a patient suffering from a fast-growing metastasis to the oral cavity, completely filling the buccal cavity within 2 weeks, as the only manifestation of recurrent glioblastoma multiforme following initial surgical resection and adjuvant RCTx.

Evaluating the Effect of Micropump© Position, Internal Pressure and Doxorubicin Dosage on Efficacy of Pressurized Intra-peritoneal Aerosol Chemotherapy (PIPAC) in an Ex Vivo Model.

BACKGROUND/AIM: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel clinical approach to the treatment of peritoneal carcinomatosis. A well-established, not anatomic ex vivo PIPAC model was used to investigate the influence of changes in internal pressure, distance of the Micropump(©) (MIP) to the distributing surface and the drug concentration on the penetration depth of doxorubicin in the target tissue. MATERIALS AND METHODS: Doxorubicin was aerosolized in an ex vivo PIPAC model using a hermetic container system mimicking the abdominal cavity. Fresh post-mortem swine peritoneum was cut into proportional samples. Tissue specimens were spatially placed at 4 different spots within the box: P1, on the distributing surface of the box, directly opposite to MIP; P2, on the side wall of the box; P3, on the ceiling of the box; P4, on the distributing surface with a partial cover. Impact of changes in the following parameters were analyzed and compared with clinically established values (CEVs) at our center: pressure (CEV=12 mmHg), distance of the MIP from the distributing surface (CEV=8 cm) and doxorubicin concentration (CEV=3 mg/50 ml). In-tissue doxorubicin penetration depth was measured using fluorescence microscopy on frozen thin sections. RESULTS: Tissue positioning in the box had a significant impact on drug penetration after PIPAC with CEV. Under CEV conditions, the highest drug penetration depth was observed in the tissue placed on the distributing surface directly opposite to the MIP (P1: 351 µm, P2: 77 µm, P3: 66 µm, P4: 34 µm). A closer positioning of the MIP lead to a significantly higher mean depth penetration of doxorubicin in the P1 in contrast to other samples in which a reduced drug penetration was observed (1 cm vs. 8 cm distance from MIP to the distributing surface, P1 at 1 cm: 469 µm vs. P1 at 8 cm: 351 µm, p<0.0001; P2 at 1 cm: 25 µm vs. P2 at 8 cm: 77 µm, p<0.0001; P3 at 1 cm: 21 µm vs. P3 at 8 cm: 66 µm, p<0.001; P4 at 1 cm: 13 µm vs. P4 at 8 cm: 39 µm, p=0.021). Higher doxorubicin concentrations led to a highly significant increase of drug penetration in P1 (1 cm vs. 8 cm, p<0.0001), but only a little significant increase in other samples. An increase of internal pressure did not show a significant increase in penetration depth of doxorubicin. CONCLUSION: Our ex vivo data suggest that a higher pressure does not increase the penetration deepness of doxorubicin. Higher drug dosage and a closer positioning of the MIP toward the target lead to a higher penetration of doxorubicin within the samples. A more homogeneous penetration within all targets cannot be achieved by changing drug concentration, position of the nozzle or pressure increase.

Distribution pattern and penetration depth of doxorubicin after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in a postmortem swine model.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel approach delivering intraperitoneal chemotherapy by means of a pressurized aerosol. This study was conducted to evaluate the distribution pattern of doxorubicin in the abdominal cavity after PIPAC in a postmortem swine model. METHODS: Doxorubicin was aerosolized through a Micropump© (MIP) into the peritoneal cavity of two swines at a pressure of 12 mm Hg CO2 and 32 °C. To measure the distribution of the drug, 9 different positions within the abdominal cavity were sampled. In-tissue doxorubicin penetration was evaluated using fluorescence microscopy on frozen thin sections. RESULTS: A maximum of drug penetration was observed in the area around the MIP. The penetration in the small intestine reached a depth of 349 ± 65 µm. Penetration depth in the right upper abdomen and left upper abdomen were 349 ± 65 and 140 µm ± 26 µm, respectively. Distant areas to the MIP showed variable penetration rates between 50 and 150 µm. CONCLUSIONS: Doxorubicin reached all areas within the peritoneum. Highest penetration rates were measured in the area around the Micropump. Further studies are warranted to evaluate and optimize the distribution and penetration of cytotoxic agent into the tissue after PIPAC.

Irradiation Does Not Increase the Penetration Depth of Doxorubicin in Normal Tissue After Pressurized Intra-peritoneal Aerosol Chemotherapy (PIPAC) in an Ex Vivo Model.

AIM: To compare the impact of single fractional with bi-fractional irradiation on the depth of doxorubicin penetration into the normal tissue after pressurized intra-peritoneal aerosol chemotherapy (PIPAC) in our ex vivo model. MATERIALS AND METHODS: Fresh post mortem swine peritoneum was cut into 12 proportional sections. Two control samples were treated with PIPAC only (no irradiation), one sample on day 1, the other on day 2. Five samples were irradiated with 1, 2, 4, 7 or 14 Gy followed by PIPAC. Four samples were treated on day one with 0.5, 1, 2, 3.5 or 7 Gy and with the same radiation dose 24 h later followed by PIPAC. Doxorubicin was aerosolized in an ex vivo PIPAC model at 12 mmHg/36°C. In-tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. RESULTS: Doxorubicin penetration (DP) after PIPAC for the control samples was 407 µm and 373 µm, respectively. DP for samples with single fraction irradiation was 396 µm after 1 Gy, 384 µm after 2 Gy, 327 µm after 4 Gy, 280 µm after 7 Gy and 243 µm after 14 Gy. DP for samples with 2 fractions of irradiation was 376 µm after 0.5+0.5 Gy, 363 µm after 1+1 Gy, 372 µm after 2+2 Gy, 341 µm after 3.5+3.5 and 301 µm after 7+7 Gy irradiation. Fractionating of the irradiation did not significantly change DP into normal tissue. CONCLUSION: Irradiation does not increase the penetration depth of doxorubicin into the normal tissue but might have a limiting impact on penetration and distribution of doxorubicin. Further studies are warranted to investigate the impact of addition of irradiation to PIPAC of tumor cells and to find out if irradiation can be used safely as chemopotenting agent for patients with peritoneal metastases treated with PIPAC.

Effect of Irradiation on Tissue Penetration Depth of Doxorubicin after Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) in a Novel Ex-Vivo Model.

BACKGROUND: This study was performed to assess the impact of irradiation on the tissue penetration depth of doxorubicin delivered during Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC). METHODS: Fresh post mortem swine peritoneum was cut into 10 proportional sections. Except for 2 control samples, all received irradiation with 1, 2, 7 and 14 Gy, respectively. Four samples received PIPAC 15 minutes after irradiation and 4 other after 24 hours. Doxorubicin was aerosolized in an ex-vivo PIPAC model at 12 mmHg/36°C. In-tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. RESULTS: Doxorubicin penetration after PIPAC (15 minutes after irradiation) was 476 ± 74 µm for the control sample, 450 ± 45µm after 1 Gy (p > 0.05), 438 ± 29 µm after 2 Gy (p > 0.05), 396 ± 32 µm after 7 Gy (p = 0.005) and 284 ± 57 after 14 Gy irradiation (p < 0.001). The doxorubicin penetration after PIPAC (24 hours after irradiation) was 428 ± 77 µm for the control sample, 393 ± 41 µm after 1 Gy (p > 0.05), 379 ± 56 µm after 2 Gy (p > 0.05), 352 ± 53 µm after 7 Gy (p = 0.008) and 345 ± 53 after 14 Gy irradiation (p = 0.001). CONCLUSIONS: Higher (fractional) radiation dose might reduce the tissue penetration depth of doxorubicin in our ex-vivo model. However, irradiation with lower (fractional) radiation dose does not affect the tissue penetration negatively. Further studies are warranted to investigate if irradiation can be used safely as chemopotenting agent for patients with peritoneal metastases treated with PIPAC.

Survival and Symptom Relief after Palliative Radiotherapy for Esophageal Cancer.

PURPOSE: The aim of this study was to assess the 6-months dysphagia-free survival, improvement in swallowing function, complication rate, and overall survival in patients with incurable esophageal cancer treated with palliative radiotherapy. METHODS: We retrospectively reviewed data from 139 patients (median age 72 years) with advanced/recurrent incurable esophageal cancer, who were referred to 3 German radiation oncology centers for palliative radiotherapy between 1994 and 2014. Radiotherapy consisted of external beam radiotherapy (EBRT) with 30 - 40.5 Gy/2.5 - 3 Gy per fraction, brachytherapy alone (BT) with 15 - 25 Gy/5 - 7Gy per fraction/weekly and EBRT + BT (30 - 40.5 Gy plus 10 - 14 Gy with BT) in 65, 46, and 28 patients, respectively. Dysphagia-free survival (Dy-PFS) was defined as the time to worsening of dysphagia for at least one point, a new loco-regional failure or death of any cause. RESULTS: Median follow-up time was 6 months (range 1-6 months). Subjective symptom relief was achieved in 72 % of patients with median response duration of 5 months. The 1-year survival rate was 30%. The 6-months Dy-PFS time for the whole group was 73 ± 4%. The 6-months Dy-PFS was 90 ± 4% after EBRT, 92 ± 5% after EBRT + BT and 37 ± 7% after BT, respectively (p<0.001). Five patients lived for more than 2 years, all of them were treated with EBRT ± BT. Ulceration, fistula and stricture developed in 3, 6 and 7 patients, respectively. CONCLUSIONS: Radiotherapy leads to symptom improvement in the majority of patients with advanced incurable esophageal cancer. The present results favor EBRT ± BT over BT alone. Due to the retrospective nature of this study, imbalances in baseline characteristics might have contributed to this finding, and further trials appear necessary.

Treatment Results of MammoSite Catheter in Combination with Whole-breast Irradiation.

AIM: To report the initial outcomes of patients treated with the MammoSite brachytherapy device (MSBT) as a boost followed by external whole-breast irradiation (WBI). PATIENTS AND METHODS: From June 2011 to March 2014, 107 patients (typically with pT1-2, pN0-1, M0 disease) were treated with breast-conserving therapy and adjuvant radiotherapy with MSBT (15 Gy in 2.5-Gy fractions) followed by WBI (median=50.4 Gy). Toxicity was classified according to the Common Terminology Criteria for Adverse Events v3.0. The median follow-up was 21 months. RESULTS: To date, no ipsilateral breast-tumor recurrences have been observed; 102 patients (95%) were alive at last follow-up. Two patients (2%) developed distant metastases. Five patients (5%) died during follow-up, only one as a result of breast cancer. The 2-year disease-free survival was 95±3%. The incidence of asymptomatic and symptomatic seroma in 90 days after MSBT was 28% and 10%, respectively. Infectious mastitis was observed in three patients (3%), who were treated successfully with antibiotics. Only three patients (3%) developed RT-induced dermatitis greater than grade 2 after WBI. CONCLUSION: The boost technique used in this study seems to provide excellent local control with acceptable toxicity, similar to the results observed with other forms of interstitial accelerated partial-breast irradiation as a boost. Long-term follow-up is necessary to refine the patient selection criteria and to assess efficacy and late toxicities.

Radiotherapy, Bisphosphonates and Surgical Stabilization of Complete or Impending Pathologic Fractures in Patients with Metastatic Bone Disease.

PURPOSE: To report the treatment outcomes of patients with metastatic bone disease with complete or impending pathologic fractures, who were treated with postoperative radiotherapy (RT), bisphosphonates or both after orthopedic stabilization. MATERIAL AND METHODS: We retrospectively evaluated the results of RT, bisphosphonates or both after orthopedic stabilization for complete or impending pathologic fractures in 72 patients with skeletal metastases. After surgery, 32 patients (44%) were treated with RT alone (group 1), 31 patients (43%) were treated with RT and bisphosphonates (group 2) and 9 (13%) patients were treated with bisphosphonates (group 3), respectively. Patients were treated with a median dose of 30Gy (30-40 Gy/2-3Gy per fraction).The local tumor progression, pain progression and need for re-operation or re-radiotherapy were assessed from patients' medical records. Median follow-up time was 9 months. RESULTS: Median overall survival time was 14 months (95% CI: 12-17). Secondary surgical intervention at the same location was necessary in 1 patient of group 1 (2%), 2 patients of group 2(5%) and 2 patients of group 3 (15%), respectively (p=0.097). Local tumor progress was observed in 3 patients of group 1 (9%), 2 patients of group 2 (7%) and 4 patients in group 3 (44%), respectively (p=0.021). Local pain progress was observed in 19%, 16% and 67% of the same groups (p=0.011). CONCLUSION: Our data confirm the efficacy and necessity of postoperative RT after orthopedic stabilization for metastatic bone disease to control the local disease. Bisphosphonates do not obviate the need for RT in the management of bone metastases after surgical stabilization. The combined treatment might lead to a better local tumor and pain control.

Outcomes of patients with squamous cell carcinoma of esophagus who did not receive surgical resection after neoadjuvant radiochemotherapy.

AIMS AND BACKGROUND: The primary objective was to assess the different reasons for refusal of surgical resection (SR) in patients with esophageal squamous cell cancer (ESCC), who were initially planned for neoadjuvant radiochemotherapy (N-RCT) + SR, but SR was not performed after N-RCT. METHODS AND STUDY DESIGN: From 1988 to 2011, 311 patients with ESCC were treated with N-RCT in a tertiary referral center for esophageal diseases. Fifty-three patients were analyzed who received RCT with 40-45 Gy and concomitant chemotherapy in neoadjuvant intention, but in whom the treatment was stopped or switched to definitive RCT due to progression, patient decision, or new findings. RESULTS: The reasons for refusal of SR for these 53 patients were as follows: (1) patients' or physicians' preference for the planned treatment was changed during the N-RCT, such that RCT was continued to a curative dose without a break (group 1, n = 23, 44%); (2) patients were restaged after 4 weeks, and the tumor board decided to continue RCT because R0 resection was unlikely and/or patients were medically unfit (group 2, n = 15, 28%); (3) patients refused continuation of any treatment (group 3, n = 15, 28%). Refusal of SR was significantly more likely in patients with longitudinal tumor dimension >8 cm and those with an Eastern Cooperative Oncology Group performance status score of 2. Median follow-up time from the start of N-RCT was 57 months (range 1-137 months). The survival rates at 2 and 5 years were 36 ± 7% and 27 ± 7%, respectively. Group 1 had significantly longer survival. CONCLUSIONS: The planned N-RCT+SR could not be completed in a considerable number of patients in a tertiary referral center. More strict selection criteria for multimodality treatment including SR could spare some of these patients an incomplete treatment and probably lead to increased utilization of definitive RCT.

The therapeutic effect of photon irradiation on viable glioblastoma cells is reinforced by hyperbaric oxygen.

BACKGROUND: Hyperbaric oxygen (HBO) seems to intensify the effect of ionising radiation. We investigated whether HBO combined with irradiation decreases the capability of U251 glioblastoma cells for relapse and metastasis. MATERIALS AND METHODS: Cells were treated with O2 at 1.3 bar and then irradiated with 2 Gy photons. Clonogenic survival was tested with colony formation. Motility is an important feature of metastasis and was measured with time-lapse videography. RESULTS: The clonogenic survival diminished by 22% through HBO, by 49% through irradiation, and by 70% through the combination of both. The accumulated distance travelled by cells fell by 3% with HBO, rose by 17% with irradiation, but was reduced by 11% with their combination. The respective values for the Euclidean distance travelled were +8%, +47% and -14%. Compared to normoxic irradiation, additional HBO lowered travel by 41%. CONCLUSION: HBO strengthens the effect of irradiation on clonogenic survival and reverses radiation-induced increase in the mobility of cells.

The prognostic value of irradiated lung volumes on the prediction of intra-/ post-operative mortality in patients after neoadjuvant radiochemotherapy for esophageal cancer. A retrospective multicenter study.

PURPOSE: To assess the association between dosimetric factors of the lung and incidence of intra- and postoperative mortality among esophageal cancer (EC) patients treated with neoadjuvant radiochemotherapy (N-RCT) followed by surgery (S). METHODS AND MATERIALS: Inclusion criteria were: age < 85 years, no distant metastases at the time of diagnosis, no induction chemotherapy, conformal radiotherapy, total dose ≤ 50.4 Gy, and available dose volume histogram (DVH) data. One-hundred thirty-five patients met our inclusion criteria. Median age was 62 years. N-RCT consisted of 36 - 50.4 Gy (median 45 Gy), 1.8 - 2 Gy per fraction. Concomitant chemotherapy consisted of 5-Fluoruracil (5-FU) and cisplatin in 113 patients and cisplatin and taxan-derivates in 15 patients. Seven patients received a single cytotoxic agent. In 130 patients an abdominothoracal and in 5 patients a transhiatal resection was performed. The following dosimetric parameters were generated from the total lung DVH: mean dose, V5, V10, V15, V20, V30, V40, V45 and V50. The primary endpoint was the rate of intra- and postoperative mortality (from the start of N-RCT to 60 days after surgical resection). RESULTS: A total of ten postoperative deaths (7%) were observed: 3 within 30 days (2%) and 7 between 30 and 60 days after surgical intervention (5%); no patient died during the operation. In the univariate analysis, weight loss (≥10% in 6 months prior to diagnosis, risk ratio: 1.60, 95%CI: 0.856-2.992, p=0.043), Eastern Cooperative Oncology Group-performance status (ECOG 2 vs. 1, risk ratio: 1.931, 95%CI: 0.898-4.150, p=0.018) and postoperative pulmonary plus non-pulmonary complications (risk ratio: 2.533, 95%CI: 0.978-6.563, p=0.004) were significantly associated with postoperative mortality. There was no significant association between postoperative mortality and irradiated lung volumes. Lung V45 was the only variable which was significantly associated with higher incidence of postoperative pulmonary plus non-pulmonary complications (Exp(B): 1.285, 95%CI 1.029-1.606, p=0.027), but not with the postoperative pulmonary complications (Exp(B): 1.249, 95%CI 0.999-1.561, p=0.051). CONCLUSIONS: Irradiated lung volumes did not show relevant associations with intra- and postoperative mortality of patients treated with moderate dose (36 - 50.4 Gy) conventionally fractionated conformal radiotherapy combined with widely used radiosensitizers. Postoperative mortality was significantly associated with greater weight loss, poor performance status and development of postoperative complications, but not with treatment-related factors. Limiting the volume of lung receiving higher radiation doses appears prudent because of the observed association with risk of postoperative complications.

Radio(chemo)therapy for locally advanced squamous cell carcinoma of the esophagus: long-term outcome.

PURPOSE: The purpose of this work is to report the long-term outcomes of three-dimensional conformal radio(chemo)therapy in the curative management of esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: A retrospective analysis of patients treated with radio(chemo)therapy between 1988 and 2011 at Klinikum rechts der Isar, Technische Universität München was performed. In all, 168 patients received radio(chemo)therapy for ESCC in curative intention. The median follow-up time was 91 months (range 1-212 months). There were 128 men and 40 women with a median age of 63 years. Selection criteria for radio(chemo)therapy were unfit for surgery and/or unresectable primary tumor (n = 146, 87 %) or patients' choice (n = 22, 13 %). The majority of the patients received a combination of cisplatin and 5-fluorouracil chemotherapy with 54 Gy in 30 fractions of radiotherapy. RESULTS: The median overall survival (OS) was 20 months (95 % confidence interval 17-23 months). The OS at 2 and 5 years for the whole cohort was 41 ± 4 % and 22 ± 3 %, respectively. Forty patients (24 %) suffered an in-field recurrence. The most common acute nonhematologic toxicity >grade 2 was dysphagia in 35 % of the patients. Acute hematologic toxicity > grade 2 was recorded in 14 % of the patients. There was no grade 5 toxicity observed during the study. Poor ECOG performance status (0-1 vs. 2-3, HR = 1.70, p = 0.002) and weight loss ≥ 10 % before the start of therapy (HR = 1.99, p = 0.001) were among the factors significantly associated with poor OS in multivariate analysis. CONCLUSION: Three-dimensional conformal definitive radio(chemo)therapy is well tolerated and leads to long-term survival in more than 20 % of patients with advanced disease and/or contraindication to surgery. However, 24 % in-field recurrence remains a major concern. Prospective trials are warranted to assess if a well-tailored conformal radiochemotherapy can improve the local control and obviate the need for surgical resection in patients with good general condition and potentially resectable tumors.

Association between radiation dose and pathological complete response after preoperative radiochemotherapy in esophageal squamous cell cancer.

AIM: This study was undertaken to examine the impact of radiation dose on pathological complete response (pCR) rates following neoadjuvant radiochemotherapy (N-RCT) for squamous cell esophageal cancer (ESCC). PATIENTS AND METHODS: From 1988 to 2011, 218 patients were treated with 30-30.6 Gy (1.8-2 Gy per fraction), 39.6-40 Gy (1.8-2 Gy per fraction) or 44-45 Gy (1.8-2 Gy per fraction) and concomitant cisplatin ± 5-fluorouracil (5-FU), oxaliplatin + 5-FU or 5-FU alone. The most commonly used concomitant chemotherapy was continuous infusion of 5-FU-alone with a dose of 300 mg/m(2)/day during the whole course of treatment (n=111). To eliminate the dispersing effect of potentially different efficacy levels of these drug regimens on pCR, we excluded patients with regimens other than 5-FU-alone. RESULTS: Histomorphological regression grade 1a (0% residual tumor), 1b (<10% residual tumor), 2 (10-50% residual tumor) and 3 (>50% residual tumor) was observed in 26 (23%), 24 (22%), 36 (32%) and 25 (23%) patients, respectively. pCR was observed in 9 out of 71 (13%) patients treated with 30 Gy-30.6 Gy, 13 of 34 (38%) patients treated with 39.6-40 Gy and 4 of 6 (67%) patients treated with 44-45 Gy (p=0.001). Median follow-up time from the start of N-RCT was 191 months (range=2-262 months). The estimated 5-year overall survival (OS) was 33% for the whole cohort. OS at 5 years was 58% for patients with pCR compared to 25% for patients with less favorable response to N-RCT (p=0.009), respectively. CONCLUSION: The dose of radiation correlates significantly with the likelihood of achieving a pCR in stage II/III squamous cell esophageal cancer patients. Prospective randomized trials are required to definitively evaluate the impact of application of higher radiation doses on efficacy and safety/tolerability in the context of N-RCT on the clinical outcomes.

Long-term outcomes of trimodality treatment for squamous cell carcinoma of the esophagus with cisplatin and/or 5-FU: more than 20 years' experience at a single institution.

PURPOSE: The purpose of this article is to report the outcome of neoadjuvant radiochemotherapy (N-RCT) + surgery in patients with squamous cell carcinoma of the esophagus at a single institution. METHODS: We retrospectively reviewed data from patients who were referred to our department for N-RCT. From 1988­2011, 103 patients were treated with N-RCT with cisplatin and/or 5-fluorouracil (5-FU). Group 1: (n = 55) from 1988­2006 with 39.6­40 Gy and 5-FU with (n = 17) or without cisplatin (n = 38). Group 2: from 2003­2010 with 44­45 Gy and 5-FU with (n = 40) or without cisplatin (n = 8). All patients underwent radical resection with reconstruction according to tumor location and 2-field lymph node dissection. The degree of histomorphologic regression was defined as grade 1a (pCR, 0 % residual tumor), grade 1b (pSTR, < 10 % residual tumor), grade 2 (10­50 % residual tumor), and grade 3 (> 50 % residual tumor). RESULTS: Median follow-up time from the start of N-RCT was 100 months (range 2­213 months). The median overall survival (OS) for the whole cohort was 42 months and the 5-year OS was 45 ± 5 %. In the multivariate analysis, worse ECOG performance status (p < 0.001), weight loss > 10 % before the start of the N-RCT (p = 0.025), higher pT category (p = 0.001), and grade 2/3 pathologic remission (p < 0.001) were significantly associated with a poor OS. PCR and pSTR rates for group 1 were 36 % and 18 % compared to 53 % and 22 % for group 2 (p = 0.011). There was a tendency for a better outcome in group 2 patients without statistical significance. The 5-year OS, disease-free survival and recurrent-free survival were 36 ± 7 %, 35 ± 6, and 36 ± 7 % for group 1 and 55 ± 7, 49 ± 7, and 53 ± 7 in group 2 (p = 0.117, p = 0.124, and p = 0.087). There was no significant difference between the two groups considering the postoperative morbidity and mortality. CONCLUSION: Higher radiation doses and more use of simultaneous cisplatin lead to higher pathologic response rates to N-RCT and may be associated with better survival outcomes. Prospective controlled trials are needed to assess the true value of intensified N-RCT regimens.