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Abstract: Purpose: To assess efficacy and tolerance of intra-operative radiation therapy (IORT) in patients suffering from locally advanced rectal cancer, treated with preoperative radiotherapy followed by surgical resection. Methods and materials: In this French, multicenter, comparative, phase III study, 142 patients with locally advanced rectal cancer (T3 or T4 or N+, and M0), treated with a 4-week preoperative radiotherapy (40 grays) were randomly assigned to either surgical resection alone (Control group: n =69) or combined to 18-gray intra-operative radiation therapy (IORT group: n =73) between 1993 and 2001. Results: The 5-year cumulative incidence of local control was 91.8% with IORT and 92.8% with surgery alone (p =0.6018); the mean duration without local relapse (Kaplan–Meier method) was 107 versus 126months, respectively. No statistically significant difference was demonstrated for overall survival (p =0.2578) disease-free survival (p =0.7808) and probability of metastatic relapse (p =0.6037) with 5-year cumulative incidences of 69.8% versus 74.8%, 63.7% versus 63.1%, and 26.1% versus 30.2%, respectively. 48 patients of the IORT group and 53 patients of the control group were alive with a median follow-up of 60.1 and 61.2months, respectively. Post-operative complications were observed in the IORT group in 21 patients (29.6%) and in the control group in 13 patients (19.1%) (p =0.15), with an acceptable tolerance profile. Conclusions: Although this randomized study did not demonstrate any significant improvement in local control and disease-free survival in rectal cancer patients treated with preoperative radiation therapy receiving IORT or not, it confirmed the technical feasibility and the necessity for evaluating IORT for rectal carcinoma in further clinical studies. [Copyright &y& Elsevier]

Summary: Introduction: Radiation recall is an inflammatory skin reaction at a previously irradiated field subsequent to the administration of a variety of pharmacologic agents. Although skin has been the major site of radiation recall toxicity, instances involving other organ have been reported. Materials and methods: Data for this review were identified by searches of Medline and Cancerlit. The search terms “radiation”, “recall”, and “toxicity” were used. References identified from within retrieved articles were also used. There was no limitation on year of publication and no abstract forms were included. Only articles published in English were taken into consideration. Results: Idiosyncratic drug hypersensitivity phenomenon is a recent hypothesis which correlates best with the available facts at this moment. The phenomenon may occur days to years after radiotherapy has been completed. The majority of the drugs commonly used in cancer therapy have been involved in the radiation recall phenomenon. A mixed non-specific inflammatory infiltrate seems to be the common histopathologic criteria in previous published reports. Universally, corticosteroids or the use of non-steroidal anti-inflammatory agents, in conjunction with withdrawal of the offending agent, produce prompt improvement. Conclusion: We propose to collect all future radiation recall phenomenon in a Rare Cancer Network database in order to augment our understanding of this rare reaction. [Copyright &y& Elsevier]

Summary Background Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results. Methods Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , number NCT02295033 . Findings Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17·2 years (IQR 13·0–19·0). 20-year overall survival was 59·7% (99% CI 56·3–63·0) in the boost group versus 61·1% (57·6–64·3) in the no boost group, hazard ratio (HR) 1·05 (99% CI 0·92–1·19, p=0·323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0·65 (99% CI 0·52–0·81, p<0·0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16·4% (99% CI 14·1–18·8) in the no boost group versus 12·0% (9·8–14·4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1·8% (99% CI 1·1–2·5) in the no boost group versus 5·2% (99% CI 3·9–6·4) in the boost group (p<0·0001). Interpretation A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years. Funding Fonds Cancer, Belgium. [ABSTRACT FROM AUTHOR]

Purpose To determine the impact of chemoradiation therapy (CRT) on overall survival (OS) after resection of pancreatic adenocarcinoma. Methods and Materials A multicenter retrospective review of 955 consecutive patients who underwent complete resection with macroscopically negative margins (R0-1) for invasive carcinoma (T1-4; N0-1; M0) of the pancreas was performed. Exclusion criteria included metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiation therapy (IORT), and a histological diagnosis of no ductal carcinoma, or postoperative death (within 60 days of surgery). In all, 623 patients received postoperative radiation therapy (RT), 575 patients received concurrent chemotherapy (CT), and 462 patients received adjuvant CT. Results Median follow-up was 21.0 months. Median OS after adjuvant CRT was 39.9 versus 24.8 months after no adjuvant CRT ( P <.001) and 27.8 months after CT alone ( P <.001). Five-year OS was 41.2% versus 24.8% with and without postoperative CRT, respectively. The positive impact of CRT was confirmed by multivariate analysis (hazard ratio [HR] = 0.72; confidence interval [CI], 0.60-0.87; P =.001). Adverse prognostic factors identified by multivariate analysis included the following: R1 resection (HR = 1.17; CI = 1.07-1.28; P <.001), higher pT stage (HR = 1.23; CI = 1.11-1.37; P <.001), positive lymph nodes (HR = 1.27; CI = 1.15-1.41; P <.001), and tumor diameter >20 mm (HR = 1.14; CI = 1.05-1.23; P =.002). Multivariate analysis also showed a better prognosis in patients treated in centers with >10 pancreatic resections per year (HR = 0.87; CI = 0.78-0.97; P =.014) Conclusion This study represents the largest comparative study on adjuvant therapy in patients after resection of carcinoma of the pancreas. Overall survival was better in patients who received adjuvant CRT. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of irradiation of internal mammary nodes (IMN) on 10-year overall survival in breast cancer patients after mastectomy. Methods and Patients: This multicenter phase 3 study enrolled patients with positive axillary nodes (pN+) or central/medial tumors with or without pN+. Other inclusion criteria were age <75 and a Karnofsky index ≥70. All patients received postoperative irradiation of the chest wall and supraclavicular nodes and were randomly assigned to receive IMN irradiation or not. Randomization was stratified by tumor location (medial/central or lateral), axillary lymph node status, and adjuvant therapy (chemotherapy vs no chemotherapy). The prescribed dose of irradiation to the target volumes was 50 Gy or equivalent. The first 5 intercostal spaces were included in the IMN target volume, and two-thirds of the dose (31.5 Gy) was given by electrons. The primary outcome was overall survival at 10 years. Disease-free survival and toxicity were secondary outcomes. Results: T total of 1334 patients were analyzed after a median follow-up of 11.3 years among the survivors. No benefit of IMN irradiation on the overall survival could be demonstrated: the 10-year overall survival was 59.3% in the IMN-nonirradiated group versus 62.6% in the IMN-irradiated group (P=.8). According to stratification factors, we defined 6 subgroups (medial/central or lateral tumor, pN0 [only for medial/central] or pN+, and chemotherapy or not). In all these subgroups, IMN irradiation did not significantly improve overall survival. Conclusions: In patients treated with 2-dimensional techniques, we failed to demonstrate a survival benefit for IMN irradiation. This study cannot rule out a moderate benefit, especially with more modern, conformal techniques applied to a higher risk population. [Copyright &y& Elsevier]

Abstract: Salvage intensity modulated radiotherapy (IMRT) to the prostate bed has hardly been studied so far. We present here a feasibility study and early clinical results for 10 patients. These patients were selected on the basis of having either a biochemical relapse or high risk histology after prostatectomy. They were treated using “sliding-window” IMRT to 68Gy in 34 fractions. Three-dimensional conformal radiotherapy (3D-CRT) plans were generated using the same planning computed tomography data set. Dose coverage of planning target volumes (PTVs) and of organs-at-risk (OAR, namely: rectum, bladder, and femoral heads) were compared. Acute toxicity and chronic toxicity were measured using the Common Toxicity Criteria for Adverse Events version 3.0 scale. IMRT significantly reduces the dose above the prescription dose given to the PTV1 (mean dose: IMRT 67.2Gy vs 3D-CRT 67.7Gy (p = 0.0137)), without altering dose coverage for PTV2 (mean dose: IMRT 68.1Gy vs 3D-CRT 68.0Gy (p = 0.3750)). Doses to OAR were lower with IMRT and differences were statistically significant (mean dose: IMRT 51.4Gy vs 3D-CRT 56.6Gy for rectum (p = 0.002), IMRT 45.1Gy vs 3D-CRT 53.1Gy for bladder (p = 0.002), and IMRT 26.1Gy vs 3D-CRT 28.4Gy for femoral heads (p = 0.0059)). There was no acute or chronic genitourinary or gastrointestinal toxicity >1 with a median follow-up of 38 months. IMRT to the prostatic fossa is feasible and reduces dose to OAR, with consequential limited toxicity. [Copyright &y& Elsevier]

Summary: Background: We did a randomised phase 3 trial assessing the benefit of addition of long-term androgen suppression with a luteinising-hormone-releasing hormone (LHRH) agonist to external irradiation in patients with prostate cancer with high metastatic risk. In this report, we present the 10-year results. Methods: For this open-label randomised trial, eligible patients were younger than 80 years and had newly diagnosed histologically proven T1–2 prostatic adenocarcinoma with WHO histological grade 3 or T3–4 prostatic adenocarcinoma of any histological grade, and a WHO performance status of 0–2. Patients were randomly assigned (1:1) to receive radiotherapy alone or radiotherapy plus immediate androgen suppression. Treatment allocation was open label and used a minimisation algorithm with institution, clinical stage of the disease, results of pelvic-lymph-node dissection, and irradiation fields extension as minimisation factors. Patients were irradiated externally, once a day, 5 days a week, for 7 weeks to a total dose of 50 Gy to the whole pelvis, with an additional 20 Gy to the prostate and seminal vesicles. The LHRH agonist, goserelin acetate (3·6 mg subcutaneously every 4 weeks), was started on the first day of irradiation and continued for 3 years; cyproterone acetate (50 mg orally three times a day) was given for 1 month starting a week before the first goserelin injection. The primary endpoint was clinical disease-free survival. Analysis was by intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00849082. Findings: Between May 22, 1987, and Oct 31, 1995, 415 patients were randomly assigned to treatment groups and were included in the analysis (208 radiotherapy alone, 207 combined treatment). Median follow-up was 9·1 years (IQR 5·1–12·6). 10-year clinical disease-free survival was 22·7% (95% CI 16·3–29·7) in the radiotherapy-alone group and 47·7% (39·0–56·0) in the combined treatment group (hazard ratio [HR] 0·42, 95% CI 0·33–0·55, p<0·0001). 10-year overall survival was 39·8% (95% CI 31·9–47·5) in patients receiving radiotherapy alone and 58·1% (49·2–66·0) in those allocated combined treatment (HR 0·60, 95% CI 0·45–0·80, p=0·0004), and 10-year prostate-cancer mortality was 30·4% (95% CI 23·2–37·5) and 10·3% (5·1–15·4), respectively (HR 0·38, 95% CI 0·24–0·60, p<0·0001). No significant difference in cardiovascular mortality was noted between treatment groups both in patients who had cardiovascular problems at study entry (eight of 53 patients in the combined treatment group had a cardiovascular-related cause of death vs 11 of 63 in the radiotherapy group; p=0·60) and in those who did not (14 of 154 vs six of 145; p=0·25). Two fractures were reported in patients allocated combined treatment. Interpretation: In patients with prostate cancer with high metastatic risk, immediate androgen suppression with an LHRH agonist given during and for 3 years after external irradiation improves 10-year disease-free and overall survival without increasing late cardiovascular toxicity. Funding: AstraZeneca; Ligue Nationale Contre le Cancer (France), through the EORTC Charitable Trust. [Copyright &y& Elsevier]

Purpose: We recently presented the intraoperative radiotherapy (IORT) technique given as a reliable alternative to conventional boost radiation after breast-conserving surgery. The low crude numbers of recurrence in elderly patients led us to investigate the feasibility and the efficacy of this procedure as a sole treatment. Methods and Materials: We included 94 patients older than 65 years in this phase II trial. Among them, 42 patients presented with all the inclusion criteria, i.e., stages pT0 to pT1 and pN0, ductal invasive unifocal carcinoma, and tumor-free margin of >2 mm. IORT was delivered using a dedicated linear accelerator. One 21-Gy fraction was prescribed and specified at the 90% isodose, using electrons. In vivo dosimetry was performed for all patients. The primary endpoint was the quality index. Secondary endpoints were quality of life, local recurrences, cosmetic results, and specific and overall rates of survival. Results: The median follow-up was 30 months (range, 12–49 months), and median age was 72 years (range, 66–80 years). The median tumor diameter was 10 mm. All patients received the total prescribed dose. No acute grade 3 toxicities were observed. Endpoints for all but one patient corresponded to acceptable quality index criteria. Pretreatment quality-of-life scores were maximal, and no significant decrease was observed during follow-up. Cosmesis was good to excellent at 6 months. Two patients experienced recurrence but underwent salvage mastectomy. Conclusion: Our results confirm that exclusive partial-breast IORT is feasible for treating early-stage breast cancer in the elderly. IORT may be considered an alternative treatment for a selected population and offers a safe one-step treatment. [Copyright &y& Elsevier]

Abstract: The EORTC 22881-10882 trial in 5178 conservatively treated early breast cancer patients showed that a 16Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. To investigate predictors for the long-term risk of fibrosis, Cox regression models of the time to moderate or severe fibrosis were developed on a random set of 1797 patients with and 1827 patients without a boost, and validated in the remaining set. The median follow-up was 10.7 years. The risk of fibrosis significantly increased (P <0.01) with increasing maximum whole breast irradiation (WBI) dose and with concomitant chemotherapy, but was independent of age. In the boost arm, the risk further increased (P <0.01) if patients had post-operative breast oedema or haematoma, but it decreased (P <0.01) if WBI was given with >6MV photons. The c-index was around 0.62. Nomograms with these factors are proposed to forecast the long-term risk of moderate or severe fibrosis. [Copyright &y& Elsevier]

Abstract: Purpose: To compare the dose coverage of planning and clinical target volume (PTV, CTV), and organs-at-risk (OAR) between intensity-modulated (3D-IMRT) and conventional conformal radiotherapy (3D-CRT) before and after internal organ variation in prostate cancer. Methods and materials: We selected 10 patients with clinically significant interfraction volume changes. Patients were treated with 3D-IMRT to 80Gy (minimum PTV dose of 76Gy, excluding rectum). Fictitious, equivalent 3D-CRT plans (80Gy at isocenter, with 95% isodose (76Gy) coverage of PTV, with rectal blocking above 76Gy) were generated using the same planning CT data set (“CT planning”). The plans were then also applied to a verification CT scan (“CT verify”) obtained at a different moment. PTV, CTV, and OAR dose coverage were compared using non-parametric tests statistics for V95, V90 (% of the volume receiving ⩾95 or 90% of the dose) and D50 (dose to 50% of the volume). Results: Mean V95 of the PTV for “CT planning” was 94.3% (range, 88–99) vs 89.1% (range, 84–94.5) for 3D-IMRT and 3D-CRT (p =0.005), respectively. Mean V95 of the CTV for “CT verify” was 97% for both 3D-IMRT and 3D-CRT. Mean D50 of the rectum for “CT planning” was 26.8Gy (range, 22–35) vs 43.5Gy (range, 33.5–50.5) for 3D-IMRT and 3D-CRT (p =0.0002), respectively. For “CT verify”, this D50 was 31.1Gy (range, 16.5–44) vs 44.2Gy (range, 34–55) for 3D-IMRT and 3D-CRT (p =0.006), respectively. V95 of the rectum was 0% for both plans for “CT planning”, and 2.3% (3D-IMRT) vs 2.1% (3D-CRT) for “CT verify” (p =non-sig.). Conclusion: Dose coverage of the PTV and OAR was better with 3D-IMRT for each patient and remained so after internal volume changes. [Copyright &y& Elsevier]

Purpose: The standard radiotherapy (RT) of breast cancer consists of 50 Gy external beam RT (EBRT) to the whole breast followed by an electron boost of 10–16 Gy to the tumor bed, but this has several cosmetic disadvantages. Intraoperative radiotherapy (IORT) could be an alternative to overcome these. Methods and Materials: We evaluated 50 women with early breast cancer operated on in a dedicated IORT facility. Median dose of 10 Gy was delivered using 9-MeV electron beams. All patients received postoperative EBRT (50 Gy in 2 Gy fractions). Late toxicity and cosmetic results were assessed independently by two physicians according to the Common Terminology Criteria for Adverse Event v3.0 grading system and the European Organization for Research and Treatment of Cancer questionnaires. Results: After a median follow-up of 9.1 years (range, 5–15 years), two local recurrences were observed within the primary tumor bed. At the time of analysis, 45 patients are alive with (n = 1) or without disease. Among the 42 disease-free remaining patients, 6 experienced Grade 2 late subcutaneous fibrosis within the boost area. Overall, the scores indicated a very good quality of life and cosmesis was good to excellent in the evaluated patients. Conclusion: Our results confirm that IORT given as a boost after breast-conserving surgery is a reliable alternative to conventional postoperative fractionated boost radiation. [Copyright &y& Elsevier]

: PurposeTumor necrosis factor-α (TNF-α) enhances X-ray killing of human tumor cells in vitro and enhances tumor control when combined with radiotherapy (RT) in animal tumor models. In multiple Phase I studies, intravenous injection of TNF-α appeared to have severe systemic side effects. To overcome these limitations, we used a bispecific antibody (BAb) directed against carcinoembryonic antigen and human TNF-α to target this cytokine in human digestive carcinoma treated with simultaneous RT.: Methods and materialsWe used human digestive carcinoma cell lines (colon cancer, LS174T, and pancreatic cancer, BxPC-3) to determine the interaction of TNF-α and RT on clonogenic cytotoxicity. Isobolograms were established to confirm additive or supra-additive effects between both treatments. LS174T and BxPC-3 cells were grafted subcutaneously at Day 0 into female nude mice (7–8 weeks old). When the tumors reached a volume of about 80 mm3, the mice were randomly assigned to treatment: Group 1, normal saline i.v. injection (control group); Group 2, TNF-α at 1 μg/i.v. injection; Group 3, BAb at 25 μg/i.v. injection; Group 4, BAb plus TNF-α (ratio 25 μg to 1 μg) i.v. injection; Group 5, local RT plus normal saline (0.5 Gy · min−1) at a total dose of 30 Gy delivered in five fractions; Group 6, local RT plus TNF-α injections 3 h before RT; Group 7, local RT plus BAb plus TNF-α co-injected 24 h before RT. Tumor growth delay was used as the end point for all groups.: ResultsIn the LS174T experiments, TNF-α added 12 h before RT showed a statistically significant decrease in the survival fraction at 2 Gy compared with RT alone (0.23 vs. 0.42 Gy, p = 0.0017). These results were largely confirmed with the BxPC-3 cell lines (0.29 vs. 0.72, p <0.00001). Isobolograms confirmed the additivity between TNF-α and RT in both cell lines. At 50% survival, the data points were within the envelope of additivity. In the LS174T and BxPC-3 xenografts, RT as a single agent (Group 5) slowed tumor progression compared with Group 1 (p <0.027 and p = 0.00001, respectively). TNF-α alone, BAb alone, or BAb plus TNF-α (Groups 2, 3, and 4) had no effect. In the LS174T model, TNF-α plus RT enhanced the delay to reach 2000 mm3 compared with RT alone but without statistical significance. This delay was significantly longer when BAb was added (p = 0.0033, for Group 6 vs. Group 7). In the BxPC-3 experiments, the median delay to reach 2000 mm3 was similar between the RT and TNF-α plus RT groups (93 days). The use of our BAb in combination with TNF-α and RT dramatically enhanced this median delay (177 days, p = 0.0013). No body weight loss was observed in any group.: ConclusionOur data could be used as a solid preclinical rationale on which to base a clinical study of locally advanced pancreatic or rectal cancers in the near future. [Copyright &y& Elsevier]

: PurposeTo overcome the systemic side effects of tumor necrosis factor alpha (TNFα) injected i.v., we used a bispecific antibody (BAb) directed against carcinoembryonic antigen (CEA) and TNFα to target this cytokine in human CEA-expressing colorectal carcinoma treated simultaneously with radiation therapy (RT).: Methods, materials, and resultsLS174T cell line was used to study the interaction of TNFα and radiation on clonogenic cytotoxicity. When TNFα (2500 U/mL) was added 12 h before RT, the surviving fraction at 2 Gy was 54% lower than that obtained with irradiation alone (0.23 vs. 0.42, respectively, p = 0.001). At 20%, 50%, or 70% survival, data points were within the envelope of additivity. Concerning in vivo experiments, RT as a single agent slowed tumor progression as compared with the control group (p = 0.027), whereas TNFα, BAb, or BAb + TNFα had no effect. BAb + TNFα + RT combination enhanced the delay for the tumor to reach 2000 mm3 as compared with RT alone (p = 0.033, for BAb + TNFα + RT group vs. RT group).: ConclusionThese results suggest that TNFα in combination with BAb and RT may be beneficial for the treatment of locally advanced colorectal cancer. [Copyright &y& Elsevier]