Prognostic Factors for Local Control in Breast Cancer After Long-term Follow-up in the EORTC Boost vs No Boost Trial: A Randomized Clinical Trial.

IMPORTANCE: Prognostic factors of ipsilateral breast tumor recurrence (IBTR) may change over time following breast-conserving therapy. OBJECTIVE: The EORTC "boost no boost" trial showed that young age and high-grade invasive carcinoma were the most important risk factors for IBTR. This study reanalyses pathological prognostic factors related to IBTR using long-term follow-up. DESIGN, SETTING, AND PARTICIPANTS: Participants included 5569 early-stage breast cancer patients, treated with breast-conserving surgery (BCS) and whole-breast irradiation (WBI), who were randomized between no boost and a 16-Gy boost in the EORTC phase III "boost no boost" trial (1989-1996). A total of 1616 patients with a microscopically complete resection (according to local pathologists), included in the central pathology review, have been analyzed in this study. Median follow-up was 18.2 years. INTERVENTIONS: No further treatment or 16-Gy boost, after BCS and 50-Gy WBI. MAIN OUTCOMES AND MEASURES: Time to ipsilateral breast tumor recurrence (IBTR) as first event. RESULTS: The 20-year cumulative incidence of IBTR in 1616 patients (160 events observed) was 15% (95% CI, 12%-17%). Young age (P < .001) and presence of ductal carcinoma in situ (DCIS) (HR, 2.15; 95% CI, 1.36-3.38; P = .001) were associated with an increased risk of IBTR in multivariable analysis. The cumulative incidence of IBTR at 20 years was 34% (95% CI, 25%-41%), 14% (95% CI, 10%-18%), and 11% (95% CI, 8%-15%), in patients 40 years or younger, 41 to 50 years and 50 years or older, respectively (P < .001). This incidence was 18% (95% CI, 14%-22%) and 9% (95% CI, 6%-12%) for tumors with and without DCIS (P < .001). High-grade tumors relapsed more frequently early during follow-up but the relative effect of age and presence of DCIS seemed stable over time. The boost reduced the 20-year IBTR incidence from 31% (95% CI, 22%-39%) to 15% (95% CI, 8%-21%) (HR, 0.37; 95% CI, 0.22-0.62; P < .001) in high-risk patients (≤50 years with DCIS present). CONCLUSIONS AND RELEVANCE: The association of high-grade invasive tumor with IBTR diminished during follow-up, while the effect of DCIS adjacent to invasive tumor seemed to remain stable. Therefore, patients with high-grade invasive tumors should be monitored closely, especially in the first 5 years, while additional DCIS is an indication for longer follow-up, emphasizing the importance of long-term trial follow-up to estimate absolute effects accurately. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02295033.

Challenges in Diagnosis and Treatment of Lung Cancer in People with Intellectual Disabilities: Current State of Knowledge.

As the life expectancy of people with intellectual disability (ID) has progressed, they have become similarly at risk of cancer as individuals of the general population. Epidemiological studies indicate a reduced incidence and mortality from lung cancer in the total population of persons with ID. However, the pattern is heterogeneous and the risk is strongly correlated with the impairment level; persons with mild intellectual impairment have higher cancer risk, and this subgroup also has the highest tobacco consumption (the major risk factor for lung cancer) compared to individuals with more severe impairment. Clinical presentation of lung cancer in persons with ID is often atypical, with symptoms frequently hidden by the mental state and communication impairments. Treatment can be impeded by incomplete understanding and lack of cooperation on the part of the patient; nevertheless, general principles for treating lung cancer must be applied to persons with ID. Early diagnosis and implementation of an adapted treatment plan may result in lung cancer outcomes similar to those of individuals in the general population. Physicians facing the difficult task of treating lung cancer in persons with ID are called to carry out their mission of care in a responsible, free, and creative way.

Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial.

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.

Multi-institutional pooled analysis on adjuvant chemoradiation in pancreatic cancer.

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.

[Partial breast irradiation]. / Radiothérapie partielle du sein.

Owing to breast cancer screening, breast cancer is more and more diagnosed at early stage. For those breast cancer women, breast conserving treatment (breast conserving surgery followed by whole breast irradiation) is commonly used since many years. New radiation modalities have been recently developed in early breast cancers particularly accelerated partial breast irradiation (APBI). Among all techniques of radiotherapy, 3D-conformal APBI and intraoperative radiotherapy (IORT) are the main modalities of radiotherapy used. The present review states on indications, treatment modalities and updated results of local control and side effects of partial breast irradiation.

Electrons for intraoperative radiotherapy in selected breast-cancer patients: late results of the Montpellier phase II trial.

BACKGROUND: The Montpellier cancer institute phase II trial started in 2004 and evaluated the feasibility of intraoperative radiotherapy (IORT) technique given as a sole radiation treatment for patients with an excellent prognostic and very low recurrence risk. METHODS: Forty-two patients were included between 2004 and 2007. Inclusion criteria were patients ≥ 65 years old, T0-T1, N0, ductal invasive unifocal carcinoma, free-margin > 2 mm. IORT was delivered using dedicated linear accelerator. One fraction of 21 Gy was prescribed and specified at the 90% isodose using electrons. In vivo dosimetry was performed for all patients. Primary end-point was the quality index. Secondary endpoints were quality of life, local recurrences, cosmetic results, specific and overall survival. RESULTS: At inclusion, median age was 72 years (range, 66-80). Median tumor diameter was 10 mm. All patients received the total prescribed dose. No acute grade 3 toxicities were observed. Late cosmetic results were good at 5 years despite the poor agreement of accuracy assessment between patients and physicians. Four patients (9.5%) experienced a local failure and underwent salvage mastectomy. The 5 year-disease free survival is 92.7% (range 79.1-97.6). All patients are still alive with a median follow-up of 72 months (range 66-74). CONCLUSION: Our results confirm with a long-term follow-up that exclusive partial breast IORT is feasible for early-breast cancer in selected patients. IORT provides good late cosmetics results and should be considered as a safe and very comfortable "one-step" treatment procedure. Nevertheless, patient assessments are essential for long-term quality results.

Simultaneous integrated boost plan comparison of volumetric-modulated arc therapy and sliding window intensity-modulated radiotherapy for whole pelvis irradiation of locally advanced prostate cancer.

Concurrent radiotherapy to the pelvis plus a prostate boost with long-term androgen deprivation is a standard of care for locally advanced prostate cancer. IMRT has the ability to deliver highly conformal dose to the target while lowering irradiation of critical organs around the prostate. Volumetric-modulated arc therapy is able to reduce treatment time, but its impact on organ sparing is still controversial when compared to static gantry IMRT. We compared the two techniques in simultaneous integrated boost plans. Ten patients with locally advanced prostate cancer were included. The planning target volume (PTV) 1 was defined as the pelvic lymph nodes, the prostate, and the seminal vesicles plus setup margins. The PTV2 consisted of the prostate with setup margins. The prescribed doses to PTV1 and PTV2 were 54 Gy in 37 fractions and 74 Gy in 37 fractions, respectively. We compared simultaneous integrated boost plans by means of either a seven coplanar static split fields IMRT, or a one-arc (RA1) and a two-arc (RA2) RapidArc planning. All three techniques allowed acceptable homogeneity and PTV coverage. Static IMRT enabled a better homogeneity for PTV2 than RapidArc techniques. Sliding window IMRT and VMAT permitted to maintain doses to OAR within acceptable levels with a low risk of side effects for each organ. VMAT plans resulted in a clinically and statistically significant reduction in doses to bladder (mean dose IMRT: 50.1 ± 4.6Gy vs. mean dose RA2: 47.1 ± 3.9 Gy, p = 0.037), rectum (mean dose IMRT: 44± 4.5 vs. mean dose RA2: 41.6 ± 5.5 Gy, p = 0.006), and small bowel (V30 IMRT: 76.47 ± 14.91% vs. V30 RA2: 47.49 ± 16.91%, p = 0.002). Doses to femoral heads were higher with VMAT but within accepted constraints. Our findings suggest that simultaneous integrated boost plans using VMAT and sliding window IMRT allow good OAR sparing while maintaining PTV coverage within acceptable levels.

Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after mastectomy.

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.

Implementing intensity modulated radiotherapy to the prostate bed: dosimetric study and early clinical results.

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 68 Gy 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 67.2 Gy vs 3D-CRT 67.7 Gy (p = 0.0137)), without altering dose coverage for PTV2 (mean dose: IMRT 68.1 Gy vs 3D-CRT 68.0 Gy (p = 0.3750)). Doses to OAR were lower with IMRT and differences were statistically significant (mean dose: IMRT 51.4 Gy vs 3D-CRT 56.6 Gy for rectum (p = 0.002), IMRT 45.1 Gy vs 3D-CRT 53.1 Gy for bladder (p = 0.002), and IMRT 26.1 Gy vs 3D-CRT 28.4 Gy 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.

Role of the radiotherapy boost on local control in ductal carcinoma in situ.

Ductal carcinoma in situ of the breast is associated with low mortality rates, but local relapse is a matter of concern in this disease. Risk factors for local relapse include young age, close or positive margins, and tumor necrosis. Whole breast irradiation following breast-conserving surgery for ductal carcinoma in situ significantly reduces the risk of local relapse as compared to breast-conserving surgery alone. Studies point to similar outcomes between breast-conserving surgery plus radiotherapy and mastectomy, in the absence of extensive disease. A complementary boost to the surgical bed improves outcomes for patients with invasive breast cancer. However, the effect of this strategy has never been prospectively reported for ductal carcinoma in situ. Two randomized controlled trials assessing this issue are ongoing. This paper represents an update on available literature about radiotherapy for DCIS with a special focus on the role of a radiotherapy boost to the tumor bed.

Three Years of Salvage IMRT for Prostate Cancer: Results of the Montpellier Cancer Center.

Background. To assess the feasibility of salvage intensity-modulated radiation Therapy (IMRT) and to examine clinical outcome. Patients and Methods. 57 patients were treated with salvage IMRT to the prostate bed in our center from January, 2007, to February, 2010. The mean prescription dose was 68 Gy in 34 fractions. Forty-four patients received concomitant androgen deprivation. Results. Doses to organs at risk were low without altering target volume coverage. Salvage IMRT was feasible without any grade 3 or 4 acute gastrointestinal or urinary toxicity. With a median follow-up of 21 months, one grade 2 urinary and 1 grade ≥2 rectal late toxicities were reported. Biological relapse-free survival was 96.5% (2.3% (1/44) relapsed with androgen suppression and 7.7% (1/13) without). Conclusion. Salvage IMRT is feasible and results in low acute and chronic side-effects. Longer follow-up is warranted to draw conclusions in terms of oncologic control.

IMRT for locally advanced anal cancer: clinical experience of the Montpellier Cancer Center.

PURPOSE: To assess outcomes of patients with carcinoma of the anal canal (CAC) treated with intensity-modulated radiation therapy (IMRT). METHOD AND MATERIALS: From August 2007 to January 2011, seventy-two patients suffering from CAC were treated with IMRT. Concurrent chemotherapy was added in case of locally advanced tumors. Radiation course consisted in delivering an initial plan to the PTV1 defined as the primary tumor and the risk area including pelvic and inguinal nodes. Forty-five Gy in daily 1.8 Gy-daily fractions were delivered five days a week. A second plan of 14.4-20 Gy to the primary tumor (PTV2) was administered in 1.8-2 Gy-daily fractions, 5 days a week. We present here the results of dosimetry, toxicities, and clinical outcome of the first 39 patients with a median follow-up of 24 months. RESULTS: Thirty-one women and eight men were included in the present analysis. Tumors were classified as stages I, II, III and IV in 2, 7, 27 and 2 patients, respectively. Median age was 59 years (range, 38-85). Radiotherapy alone (RT) or combined with chemotherapy (RCT) were delivered in 6 (15%) and 33 (85%) patients, respectively.Six patients (15%) required a treatment break ≥ 3 days, and median time for treatment break was 8 days (range, 3-14 days). Acute grade 3 gastrointestinal (GI) and genitourinary (GU) toxicities were seen in 10 and 5% of patients, respectively. Grade 4 toxicity was only hematologic and occurred in 12% patients receiving RCT. With a median follow-up of 24 months, no patient experienced any late grade 4 toxicity. The 2-year overall survival rate was 89%, the 2-year local relapse free survival was 77% and the 2-year colostomy-free survival rate was 85%. CONCLUSION: IMRT is well tolerated with acceptable treatment interruption allowing dose escalation.

Bilateral kidney preservation by volumetric-modulated arc therapy (RapidArc) compared to conventional radiation therapy (3D-CRT) in pancreatic and bile duct malignancies.

BACKGROUND: To compare volumetric-modulated arc therapy plans with conventional radiation therapy (3D-CRT) plans in pancreatic and bile duct cancers, especially for bilateral kidney preservation. METHODS: A dosimetric analysis was performed in 21 patients who had undergone radiotherapy for pancreatic or bile duct carcinoma at our institution. We compared 4-field 3D-CRT and 2 arcs RapidArc (RA) plans. The treatment plan was designed to deliver a dose of 50.4 Gy to the planning target volume (PTV) based on the gross disease in a 1.8 Gy daily fraction, 5 days a week. Planning objectives were 95% of the PTV receiving 95% of the prescribed dose and no more than 2% of the PTV receiving more than 107%. Dose-volume histograms (DVH) for the target volume and the organs at risk (right and left kidneys, bowel tract, liver and healthy tissue) were compared. Monitor units and delivery treatment time were also reported. RESULTS: All plans achieved objectives, with 95% of the PTV receiving ≥ 95% of the dose (D95% for 3D-CRT = 48.9 Gy and for RA = 48.6 Gy). RapidArc was shown to be superior to 3D-CRT in terms of organ at risk sparing except for contralateral kidney: for bowel tract, the mean dose was reduced by RA compared to 3D-CRT (16.7 vs 20.8 Gy, p = 0.0001). Similar result was observed for homolateral kidney (mean dose of 4.7 Gy for RA vs 12.6 Gy for 3D-CRT, p < 0.0001), but 3D-CRT significantly reduced controlateral kidney dose with a mean dose of 1.8 Gy vs 3.9 Gy, p < 0.0007. Compared to 3D-CRT, mean MUs for each fraction was significantly increased with RapidArc: 207 vs 589, (p < 0.0001) but the treatment time was not significantly different (2 and 2.66 minutes, p = ns). CONCLUSION: RapidArc allows significant dose reduction, in particular for homolateral kidney and bowel, while maintaining target coverage. This would have a promising impact on reducing toxicities.

Eight years of IMRT quality assurance with ionization chambers and film dosimetry: experience of the Montpellier Comprehensive Cancer Center.

BACKGROUND: To present the results of quality assurance (QA) in IMRT of film dosimetry and ionization chambers measurements with an eight year follow-up. METHODS: All treatment plans were validated under the linear accelerator by absolute and relative measures obtained with ionization chambers (IC) and with XomatV and EDR2 films (Kodak). RESULTS: The average difference between IC measured and computed dose at isocenter with the gantry angle of 0° was 0.07 ± 1.22% (average ± 1 SD) for 2316 prostate, 1.33 ± 3.22% for 808 head and neck (h&n), and 0.37 ± 0.62% for 108 measurements of prostate bed fields. Pelvic treatment showed differences of 0.49 ± 1.86% in 26 fields for prostate cases and 2.07 ± 2.83% in 109 fields of anal canal.Composite measurement at isocenter for each patient showed an average difference with computed dose of 0.05 ± 0.87% for 386 prostate, 1.49 ± 1.86% for 158 h&n, 0.37 ± 0.34% for 23 prostate bed, 0.80 ± 0.28% for 4 pelvis, and 2.31 ± 0.56% for 17 anal canal cases. On the first 250 h&n analyzed by film in absolute dose, the average of the points crossing a gamma index 3% and 3 mm was 93%. This value reached 99% for the prostate fields. CONCLUSION: More than 3500 beams were found to be within the limits defined as validated for treatment between 2001 and 2008.

Intra-operative radiotherapy of rectal cancer: results of the French multi-institutional randomized study.

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 126 months, 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 61.2 months, 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.

External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.

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.

Plan comparison of volumetric-modulated arc therapy (RapidArc) and conventional intensity-modulated radiation therapy (IMRT) in anal canal cancer.

BACKGROUND: To compare volumetric-modulated arc therapy (RapidArc) plans with conventional intensity-modulated radiation therapy (IMRT) plans in anal canal cancers. METHODS: Ten patients with anal canal carcinoma previously treated with IMRT in our institution were selected for this study. For each patient, three plans were generated with the planning CT scan: one using a fixed beam IMRT, and two plans using the RapidArc technique: a single (RA1) and a double (RA2) modulated arc therapy. The treatment plan was designed to deliver in one process with simultaneous integrated boost (SIB) a dose of 59.4 Gy to the planning target volume (PTV2) based on the gross disease in a 1.8 Gy-daily fraction, 5 days a week. At the same time, the subclinical disease (PTV1) was planned to receive 49.5 Gy in a 1.5 Gy-daily fraction. Plans were normalized to 99% of the PTV2 that received 95% of the prescribed dose. Planning objectives were 95% of the PTV1 will receive 95% of the prescribed dose and no more than 2% of the PTV will receive more than 107%. Dose-volume histograms (DVH) for the target volume and the organs at risk (bowel tract, bladder, iliac crests, femoral heads, genitalia/perineum, and healthy tissue) were compared for these different techniques. Monitor units (MU) and delivery treatment time were also reported. RESULTS: All plans achieved fulfilled objectives. Both IMRT and RA2 resulted in superior coverage of PTV than RA1 that was slightly inferior for conformity and homogeneity (p < 0.05).Conformity index (CI95%) for the PTV2 was 1.15 ± 0.15 (RA2), 1.28 ± 0.22 (IMRT), and 1.79 ± 0.5 (RA1). Homogeneity (D5% - D95%) for PTV2 was 3.21 ± 1.16 Gy (RA2), 2.98 ± 0.7 Gy (IMRT), and 4.3 ± 1.3 Gy (RA1). RapidArc showed to be superior to IMRT in terms of organ at risk sparing. For bowel tract, the mean dose was reduced of 4 Gy by RA2 compared to IMRT. Similar trends were observed for bladder, femoral heads, and genitalia. The DVH of iliac crests and healthy tissue resulted in comparable sparing for the low doses (V10 and V20). Compared to IMRT, mean MUs for each fraction was significantly reduced with RapidArc (p = 0.0002) and the treatment time was reduced by a 6-fold extent. CONCLUSION: For patients suffering from anal canal cancer, RapidArc with 2 arcs was able to deliver equivalent treatment plan to IMRT in terms of PTV coverage. It provided a better organ at risk sparing and significant reductions of MU and treatment time per fraction.

Intraoperative radiotherapy in early-stage breast cancer: results of the montpellier phase II trial.

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.

Single nucleotide polymorphisms, apoptosis, and the development of severe late adverse effects after radiotherapy.

PURPOSE: Evidence has accumulated in recent years suggestive of a genetic basis for a susceptibility to the development of radiation injury after cancer radiotherapy. The purpose of this study was to assess whether patients with severe radiation-induced sequelae (RIS; i.e., National Cancer Institute/CTCv3.0 grade, > or =3) display both a low capacity of radiation-induced CD8 lymphocyte apoptosis (RILA) in vitro and possess certain single nucleotide polymorphisms (SNP) located in candidate genes associated with the response of cells to radiation. EXPERIMENTAL DESIGN: DNA was isolated from blood samples obtained from patients (n = 399) included in the Swiss prospective study evaluating the predictive effect of in vitro RILA and RIS. SNPs in the ATM, SOD2, XRCC1, XRCC3, TGFB1, and RAD21 genes were screened in patients who experienced severe RIS (group A, n = 16) and control subjects who did not manifest any evidence of RIS (group B, n = 18). RESULTS: Overall, 13 and 21 patients were found to possess a total of <4 and > or =4 SNPs in the candidate genes. The median (range) RILA in group A was 9.4% (5.3-16.5) and 94% (95% confidence interval, 70-100) of the patients (15 of 16) had > or =4 SNPs. In group B, median (range) RILA was 25.7% (20.2-43.2) and 33% (95% confidence interval, 13-59) of patients (6 of 18) had > or =4 SNPs (P < 0.001). CONCLUSIONS: The results of this study suggest that patients with severe RIS possess 4 or more SNPs in candidate genes and low radiation-induced CD8 lymphocyte apoptosis in vitro.

Predictors of the risk of fibrosis at 10 years after breast conserving therapy for early breast cancer: a study based on the EORTC Trial 22881-10882 'boost versus no boost'.

The EORTC 22881-10882 trial in 5178 conservatively treated early breast cancer patients showed that a 16 Gy 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 >6 MV 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.