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Purpose: To determine whether DNA-dependent protein kinase (DNA-PK) and poly(ADP-ribose) polymerase (PARP-1) are involved in eliciting the rapid fluctuations of radiosensitivity that have been observed when cells are exposed to short pulses of ionizing radiation. Materials and methods: The effect of DNA-PK and PARP-1 inhibitors on the survival of cells to split-dose irradiation was investigated using Chinese hamster V79 fibroblasts and human carcinoma SQ-20B cells. The responses of PARP-1 proficient and PARP-1 knockout mouse 3T3 fibroblasts were compared in a similar split-dose assay. Results: Inactivation of DNA-PK by wortmannin potentiated radiation-induced cell kill but it did not alter the oscillatory, W-shaped pattern of early radiation response. In contrast, oscillatory radiation response was abolished by 3-aminobenzamide, a reversible inhibitor of enzymes containing a PARP catalytic domain. The oscillatory response was also lacking in PARP-1 knockout mouse 3T3 fibroblasts. Conclusion: The results show that PARP-1 plays a key role in the earliest steps of cell response to ionizing radiation with clonogenic ability or growth as endpoint. It is hypothesized that rapid poly(ADP-ribosylation) of target proteins, or recruitment of repair proteins by activated PARP-1 at the sites of DNA damage, bring about rapid chromatin remodelling that may affect the incidence of chromosomal damage upon re-irradiation. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether the oscillatory changes of radiosensitivity which occur within fractions of a second to a few minutes following flash irradiation correlate with an altered incidence of apoptosis, DNA strand breaks or lipid-coupled signalling. Materials and methods: Human tumor cells (SQ-20B, LoVo) or Chinese hamster V79 fibroblasts were exposed to split-dose, pulse irradiation with 3.5 MeV electrons at high dose-rate (12 or 120Gys[sup -1]) and the effects assessed by clonogenic assays, analysis of DNA cleavage and microscopic observation. Results: The processes underlying oscillatory radiation response were saturable, but did not correlate with an increased incidence of DNA single- or double-strand breaks or apoptosis. N-acetylcysteine and inhibitors of lipid-derived signalling also failed to alter oscillatory response. However, this response did correlate with phenotypic alterations evoking mitotic or delayed cell death. Furthermore, high dose-rate irradiation provided a lower level of instability than protracted γ-ray irradiation. Conclusions: It is proposed that the early steps of DNA damage recognition and repair following priming radiation exposure bring about rapid, synchronous remodeling of chromatin, evoking enhanced chromosome damage upon re-irradiation. [ABSTRACT FROM AUTHOR]

Radical prostatectomy (RP) is one of the recommended option for localized prostate cancer (PCa) treatment but no clear recommendations guide post-operative treatment patients with persistently elevated prostate-specific antigen (PSA) after RP. The aim of this trial was to compare immediate salvage radiation therapy (iSRT) with or without short-term androgen deprivation therapy (ADT) in these patients. RP patients with nonmetastatic PCa on conventional preoperative imaging, and with a post-RP PSA level between 0.2 and 2 ng/mL were randomized (1:1) to iSRT alone (iSRT arm) or 6 months of ADT (degarelix) with iSRT (iSRT+ADT arm). ISRT consisted of pelvic irradiation (46 Gy in 23 Fr) with a boost on the prostate bed (66 Gy in 33 Fr). The primary endpoint was event-free survival (EFS). Biochemical progression-free survival (bPFS), metastates-free survival (MFS), overall survival (OS), quality of life, and toxicities were evaluated as secondary endpoints. From Jan-2013 to Sept-2015, 125 pts were included (iSRT arm: 64 pts; iSRT+ADT arm: 61). Median follow up was 75.0 months (95% CI: 74.1-76.6). The baseline characteristics were well-balanced between the two arms. Median PSA was 0.6 ng/mL (0.12-3.65) at randomization. All patients received the planned iSRT and 98.4% in the arm iSRT+ADT received ADT as planned. The efficacy results were analyzed at 5 years. EFS was 62.3% (95% CI: 48.9-73.2) in iSRT arm and 63.5% (95% CI: 49.9-74.2) in iSRT+ADT arm (HR=0.83; 95%CI: 0.47-1.47; p=0.528). bPFS was 62.3% (95% CI: 48.9-73.2) in iSRT arm and 66% (95% CI: 52.3-76.6) in iSRT+ADT arm (HR=0.76; 95%CI: 0.44-1.31; p=0.322). MFS was in favor of the iSRT+ADT arm with HR=0.51 (95% CI: 0.26-0.99; p=0.048). OS data were not mature at the time of analysis. Multivariate analysis demonstrated that PSA level <0.6 ng/ml at randomization and tumor ≤pT3a were associated with increased bPFS (HR=1.84; 95%CI: 1.02-3.33; p=0.05 and HR=2.96; 95%CI: 1.66-5.25; p=0.0002, respectively). PSA level <0.6 ng/ml at randomization was associated with improved MFS (HR=2.82; 95%CI: 1.14-6.95; p=0.019). No grade 4 toxicities were observed. Overall, no difference in acute toxicity were observed between the 2 arms and more late toxicities (≥6 months after iSRT) were observed in the iSRT+ADT than the iSRT arm (53.1% vs 70.5%; p=0.046). At 12 months ADT-related symptoms were more important in the iSRT+ADT arm (QLQ-PR25; p=0.04). At 24 months, no difference in QLQ-C30 or QLQ-PR25 analysis was reported. After an initial 25-fold decrease in blood testosterone level, all patients recovered to normal level 12 months after starting ADT. Despite the lack of differences in terms of EFS between the two arms, this study demonstrated that iSRT+ADT improved MFS without impaired quality-of-life for patients with persistently elevated PSA after RP. [ABSTRACT FROM AUTHOR]

Curative radiotherapy for prostate cancer is common in the elderly. However, concerns about potential toxicity have inhibited access to radiotherapy for this population, for whom preserving quality of life (QoL) is crucial. The primary endpoint was to identify predictors of impaired QoL in men aged 75 years or older treated with curative intent radiotherapy with or without androgen deprivation therapy (ADT) for localized prostate cancer. We prospectively performed comprehensive geriatric assessment (CGA) and administered QoL questionnaires to 208 elderly (>75 years) patients prior to, plus two and six months after, radiotherapy (NCT02876237). The median age of the patients was 77 years (range 75-89). At the start of the study, comorbidities were highlighted in 65% of patients: 23% were depressed, 23% had cognitive impairment, and 16% had reduced independence. At six months, 9% of patients had a consistently decreased QoL (>20 points), and a further 16% had a more moderate reduction (10 to 20 points) in QoL. None of the parameters studied (tumor characteristic, treatment, or oncogeriatric parameters) were predictive of a reduced QoL following radiotherapy. Though co-existing geriatric impairment was common, QoL was maintained for 75% of patients six months after radiotherapy. CGA was poorly predictive of tolerance of prostatic radiotherapy. Geriatric assessments dedicated to quality of life following radiotherapy need to be developed.

Introduction: Radiotherapy can diminish quality of life (QoL) for prostate cancer patients. Our objective was to evaluate the effect of radiotherapy on QoL in men aged 75 years or older treated with radiotherapy for a localized prostate cancer, and to identify predictors of reduced QoL., Patients and Methods: We prospectively administered a battery of geriatric (MNA, GDS, Get up and Go Test, CIRS-G, ADL, IADL, MMSE), toxicity (IPSS; IIEF 5), and QoL (QLQ C30) screening tests in 100 elderly patients before and two months after prostate cancer radiotherapy (NCT 02876237). Patients ≥ 75 years undergoing radiotherapy with a curative intent for localized prostate cancer with or without androgen deprivation therapy (ADL) were eligible for study inclusion. Correlations between patient-assessed QoL and tumor characteristics, radiotherapy treatment or CGA parameters were sought using the Fisher or the Mann and Whitney tests. Changes in QoL parameters over time were analyzed using the Wilcoxon signed-rank test., Results: At study entry, scores for IADL impairments were present in 51%, reduced autonomy in activities of daily living in 16%, cognitive impairment found in 20%, depression-related symptoms in 31%, and 66% of patients had significant co-morbidities. Eight percent were judged to be at risk of fall and 2% were found to be undernourished. Severely impaired (IPSS ≥ 20) urinary function was observed in 11.2% and 13.5% of patients before and two months after completion of radiotherapy respectively. Significantly decreased QoL (> 20 points) at two months after treatment was found in 13% of patients and a moderate but clinically relevant reduction (10 to 20 points) in 17% of patients. No tumor characteristic, treatment, or oncogeriatric parameter was predictive of reduced QoL following prostate cancer radiotherapy., Conclusion: Despite sometimes markedly diminished oncogeriatric parameters, prostate cancer radiotherapy was generally well tolerated in these elderly patients. We found no predictive factor to determine which patients would experience impaired quality of life following radiotherapy.

Objective: Primary uterine leiomyosarcomas (ULMS) are rare, and the optimal treatment is controversial. We aimed to assess the outcome and prognostic factors in a multicenter population of women treated for primary ULMS., Methods: We retrospectively collected data of 110 women treated in 19 institutions of the Rare Cancer Network (RCN). Inclusion criteria consisted of a pathology report confirming the diagnosis of ULMS, aged 18-80 years, complete International Federation of Gynecology and Obstetrics (FIGO) stage information, complete information on treatment, and a minimum follow-up of 6 months. Local control (LC) and locoregional control (LRC), overall survival (OS) and disease-free survival (DFS) rates were computed using the Kaplan-Meier method. Univariate analysis was implemented using the log rank test, and multivariate analysis using the Cox model., Results: All patients underwent surgery. Seventy-five patients (68%) received adjuvant radiotherapy (RT), including brachytherapy in 18 (16%). Seventeen patients (15%) received adjuvant chemotherapy. Median follow-up was 58 (range, 6-240) months. Five-year OS and DFS rates were 50% and 34%, and LC and LRC rates were 88% and 72%, respectively. On multivariate analysis, independent favorable prognostic factors were younger age, FIGO stage I, small tumor size, previous uterine disease, and no vascular invasion for OS and DFS. FIGO stage was the only favorable factor influencing LRC. Adjuvant local or systemic treatments did not improve the outcomes. Eight patients treated with RT presented a grade 3 acute toxicity, and only one patient with grade 3 late toxicity., Conclusions: In this large population of primary ULMS patients, we found good results in terms of LC and LRC. Nevertheless, OS remains poor, mainly due to the occurrence of distant metastases. An early diagnosis seemed to improve the prognosis of the patients. Adjuvant local or systemic treatments, or more aggressive surgical procedures such as the Wertheim procedure, did not seem to impact the outcome.

Positron Emission Tomography (PET) is a significant advance in cancer imaging with great potential for optimizing radiation therapy (RT) treatment planning and thereby improving outcomes for patients. The use of PET and PET/CT in RT planning was reviewed by an international panel. The International Atomic Energy Agency (IAEA) organized two synchronized and overlapping consultants' meetings with experts from different regions of the world in Vienna in July 2006. Nine experts and three IAEA staff evaluated the available data on the use of PET in RT planning, and considered practical methods for integrating it into routine practice. For RT planning, (18)F fluorodeoxyglucose (FDG) was the most valuable pharmaceutical. Numerous studies supported the routine use of FDG-PET for RT target volume determination in non-small cell lung cancer (NSCLC). There was also evidence for utility of PET in head and neck cancers, lymphoma and in esophageal cancers, with promising preliminary data in many other cancers. The best available approach employs integrated PET/CT images, acquired on a dual scanner in the radiotherapy treatment position after administration of tracer according to a standardized protocol, with careful optimization of images within the RT planning system and carefully considered rules for contouring tumor volumes. PET scans that are not recent or were acquired without proper patient positioning should be repeated for RT planning. PET will play an increasing valuable role in RT planning for a wide range of cancers. When requesting PET scans, physicians should be aware of their potential role in RT planning.

Purpose: The management of locally advanced (LA) pancreatic cancer patients remains controversial. To select patients who could benefit from chemoradiotherapy (CRT), the therapeutic strategy used by the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) consisted of initial chemotherapy (CT) for at least 3 months. The decision to administer CRT or continue CT in nonprogressive patients was the investigator's choice., Patients and Methods: Retrospective analysis of outcome in 181 patients with LA pancreatic cancer (76 women and 105 men; mean age, 61 years; range, 37 to 85 years) enrolled onto prospective phase II and III GERCOR studies was performed to compare the survival of patients who received CRT with that of patients who continued CT alone., Results: Median progression-free survival (PFS) and overall survival (OS) times for the 181 patients were 6.3 and 11.4 months, respectively. Fifty-three patients (29.3%) had metastatic disease after 3 months of CT and were not eligible for CRT. Among the 128 remaining patients (70.3%) who had no disease progression and who were, therefore, eligible for CRT, 72 (56%) received CRT (group A), whereas 56 (44%) continued with CT (group B). The two groups were balanced for initial characteristics (performance status, sex, age, and type of CT), as well as for induction CT results. In groups A and B, the median PFS times were 10.8 and 7.4 months, respectively (P = .005), and the median OS times were 15.0 and 11.7 months, respectively (P = .0009)., Conclusion: These results suggest that, after control of disease by initial CT, CRT could significantly improve survival in patients with LA pancreatic cancer compared with CT alone. A prospective phase III study is ongoing to evaluate this strategy.

Purpose: To report a retrospective study concerning the impact of fused 18F-fluoro-deoxy-D-glucose (FDG)-hybrid positron emission tomography (PET) and CT images on three-dimensional conformal radiotherapy planning for patients with non-small-cell lung cancer., Methods and Materials: A total of 101 patients consecutively treated for Stage I-III non-small-cell lung cancer were studied. Each patient underwent CT and FDG-hybrid PET for simulation treatment in the same treatment position. Images were coregistered using five fiducial markers. Target volume delineation was initially performed on the CT images, and the corresponding FDG-PET data were subsequently used as an overlay to the CT data to define the target volume., Results: 18F-fluoro-deoxy-D-glucose-PET identified previously undetected distant metastatic disease in 8 patients, making them ineligible for curative conformal radiotherapy (1 patient presented with some positive uptake corresponding to concomitant pulmonary tuberculosis). Another patient was ineligible for curative treatment because the fused PET-CT images demonstrated excessively extensive intrathoracic disease. The gross tumor volume (GTV) was decreased by CT-PET image fusion in 21 patients (23%) and was increased in 24 patients (26%). The GTV reduction was > or = 25% in 7 patients because CT-PET image fusion reduced the pulmonary GTV in 6 patients (3 patients with atelectasis) and the mediastinal nodal GTV in 1 patient. The GTV increase was > or = 25% in 14 patients owing to an increase in the pulmonary GTV in 11 patients (4 patients with atelectasis) and detection of occult mediastinal lymph node involvement in 3 patients. Of 81 patients receiving a total dose of > or = 60 Gy at the International Commission on Radiation Units and Measurements point, after CT-PET image fusion, the percentage of total lung volume receiving >20 Gy increased in 15 cases and decreased in 22. The percentage of total heart volume receiving >36 Gy increased in 8 patients and decreased in 14. The spinal cord volume receiving at least 45 Gy (2 patients) decreased. Multivariate analysis showed that tumor with atelectasis was the single independent factor that resulted in a significant effect on the modification of the size of the GTV by FDG-PET: tumor with atelectasis (with vs. without atelectasis, p = 0.0001)., Conclusion: The results of our study have confirmed that integrated hybrid PET/CT in the treatment position and coregistered images have an impact on treatment planning and management of non-small-cell lung cancer. However, FDG images using dedicated PET scanners and respiration-gated acquisition protocols could improve the PET-CT image coregistration. Furthermore, the impact on treatment outcome remains to be demonstrated.

Purpose: To study the impact of fused (18)F-fluoro-deoxy-D-glucose (FDG)-hybrid positron emission tomography (PET) and computed tomography (CT) images on conformal radiotherapy planning for esophageal carcinoma patients., Methods and Materials: Thirty-four esophageal carcinoma patients were referred for concomitant radiotherapy and chemotherapy with radical intent. Each patient underwent CT and FDG-hybrid PET for simulation treatment in the same treatment position. PET images were coregistered using five fiducial markers. Target delineation was initially performed on CT images, and the corresponding PET data were subsequently used as an overlay to CT data to define the target volume., Results: (18)F-fluorodeoxy-D-glucose-PET identified previously undetected distant metastatic disease in 2 patients, making them ineligible for curative conformal radiotherapy. The gross tumor volume (GTV) was decreased by CT and FDG image fusion in 12 patients (35%) and increased in 7 patients (21%). The GTV reduction was > or =25% in 4 patients owing to a reduction in the length of the esophageal tumor. The GTV increase was > or =25% with FDG-PET in 2 patients owing to the detection of occult mediastinal lymph node involvement in 1 patient and an increased length of the esophageal tumor in 1 patient. Modifications of the GTV affected the planning treatment volume in 18 patients. Modifications of the delineation of the GTV and displacement of the isocenter of the planning treatment volume by FDG-PET also affected the percentage of total lung volume receiving >20 Gy in 25 patients (74%), with a dose reduction in 12 patients and dose increase in 13., Conclusion: In our study, CT and FDG-PET image fusion appeared to have an impact on treatment planning and management of esophageal carcinoma. The affect on treatment outcome remains to be demonstrated.

Since the end of the sixties, conservative radiosurgical treatment is the standard for unifocal breast cancers < 3 cm. Retrospective and randomised trials confirmed identical survival, but an increased second failure's rate. Impact of this local failure on survival is controversy. Different prognostic factors were identified by the authors. Local extension of the local failure and inflammatory signs, the delay of its apparition and its site (witch could difference true local failure and new tumour) the histologic type of the local failure, the phase S cells rate, the N status, and characteristics of the initial tumour such as the N status, the tumour's size. The surgical treatment of the local failure is classically the salvage mastectomy associated with immediate breast reconstruction, often by cutaneous-muscular flaps. A second conservative treatment could eventually be proposed only if breast size and radiotherapy sequels would permit a second carcinologic and cosmetic surgical treatment: wide local excision and re-irradiation, unifocal tumour < 1 cm preferentially intraductal, well differentiated without lymphovascular embole, without extensive intraductal, second new cancer (in other quadrant than the initial tumor after a long enough delay), efficient and long time survey. RMN with identification of the prognostic criteria would contribute to identify the local failure witch could benefit of an iterative conservative treatment.

The coregistration of planning CT and 18F-fluoro-deoxy-2-glucose (FDG) positron emission tomography (PET) with patient in the same treatment position is the principally well-established tool for improving the target coverage defined and the target planning volume to treat the metabolic target volume. Most of the interest in the coresgistred CT/PET images on volume delineation has focused on conformal radiation therapy of non-small cell lung cancer. In spite of technical difficulties related to the target volume displacements, and the sensitivity and the specificity of FDG-PET images < 100%, the target volume delineation is significantly changed by the coregistration of FDG-PET images and planning CT by either reduction of the radiation volume (excluding atelectasis or mediastinal lymph node) or the increasing of mediastinal lymph node involvement. Image fusion technique reduces the interobserver variability in target volume delineation. Furthermore, after induction chemotherapy image fusion leads to improve the patient management by detecting locoregional progression disease or the presence of metastatic disease. Other anatomic tumor sites are going to investigate such as: head-and-neck cancer, gynecologic cancer, oesophageal cancer, anal cancer, Hodgkin's disease, and non-Hodgkin's lymphoma. The impact on treatment outcome remains to be demonstrated.

Since 1980, curative-intent radiation therapy of epidermoid carcinoma of the anal canal is the standard first line treatment. The combined concomitant chemotherapy and radiation therapy is presently established for locally advanced tumors more than 4 cm in length and/or with nodal involvement. We report the Tenon hospital experience since 1972 concerning the long term results after radiation therapy, the modifications of the radiation technique, and the evolution of treatment strategy.

Purpose: To evaluate the efficacy and outcome of Linac radiosurgery (RS) as treatment of cerebral arteriovenous malformations (cAVM) in a series of 57 children., Methods and Materials: Between 1984 and 2000, we used Linac radiosurgery to treat 792 patients with cAVM. This series included 57 children (7.2%) under the age of 15 years at the time of RS (range = 7-15 years, median = 12 years). We were able to evaluate 49 of the children (86%) by angiography, 21 boys and 28 girls (sex ratio = 0.75). First symptoms were: hemorrhage, 34 patients (69.4%); seizures, 6 patients (12.5%); headache, 6 patients (12.5%); and progressive neurologic deficit, 1 patient (2.1%). Nidus size ranged from 5 to 50 mm (median = 20 mm). Nidus volume ranged from 0.6 to 16 cc (median = 3.5 cc). Patient distribution according to Spetzler-Martin grade was as follows: Grade 1, n = 5 (11%); Grade 2, n = 18 (35%); Grade 3, n = 21 (40%,); Grade 4, n = 5 (14%); and Grade 5, n = 0%. Twenty-seven patients (55.1%) had other treatment before RS: embolization, n = 14 (31.1%); neurosurgery, n = 9 (20.5%); embolization and neurosurgery, n = 3 (6.1%). RS was performed with the system used for adults. Patients were seated in a Betti armchair. Circular 15 MV X-ray minibeams (6 to 20 mm) were delivered in coronal arcs by a GECGR Saturne 43 Linac. Planification and dosimetry were carried out using the Associated Target Methodology and Dosigray TPS dosimetric systems. The dose at the peripheral isodose (50-70%) ranged from 18 to 28 Gy. Median and mean doses were 25 Gy and 23.8 Gy. Mono-isocentric planification was used in 25 patients (53.2%) and multi-isocentric in 24 patients (2 to 5 isocenters). The overall follow-up ranged from 7 to 172 months (mean 40 months, median 34 months)., Results: The overall rate of obliteration (OR) was 30/49 (61.2%). Mean time to obliteration was 34 months (range = 7 to 172 months). OR varied according to nidus size and volume: OR was 80% for nidus <15 mm, 67% for nidus between 15 and 25 mm, and 42% for nidus >25 mm (p = 0.058). OR was 100% for nidus <1 cc, 73% for nidus between 1 and 4 cc, and 40% for nidus of 4 to 10 cc (p = 0.019). OR according to patient gender was 84.2% for boys and 40% for girls. OR according to minimum dose (Dmin) was 44% for Dmin < 15 Gy (p = 0.01), 89% for D min from 15 to 20 Gy, and 100% for Dmin > 20 Gy (p = 0.01). OR was 62% in nonembolized AVM and 58% in previously embolized AVM (NS). OR according to the number of isocenters was 68.2%, 55.6%, 80%, 50%, and 0% for 1, 2, 3, 4, and 5 isocenters, respectively. After multivariate analysis, only Dmin closely correlated with OR (beta = 0.462; SE = 0.244, p = 0.057). Of the 6 patients with seizures before RS, 5 (80%) were seizure-free without medication after RS. One patient died of pneumonia., Morbidity: Four patients (8.2%) had bleeding after RS at 39, 45, 51, and 59 months. No new neurologic deficit was found during the follow-up period. Twenty-nine patients underwent magnetic resonance imaging. Thirteen patients (44.8%) showed no parenchymal changes. Thirteen patients (44.8%) had Grade 2 changes, that is, T2 hypersignals. Two patients (6.9%) had Grade 3 changes, and 1 patient (3.4%) had Grade 4 "necrosis-like" changes., Conclusion: In our experience, Linac RS has proven to be a safe and effective method to treat cerebral AVM in children <15 years, whether used alone or in association with embolization and/or neurosurgery.

Purpose: To identify prognostic factors and treatment toxicity in a serie of epidermoid cancers of the anal canal without evident metastasis., Patients and Methods: Between June 1972 and January 1997, 305 patients (pts) were treated with curative-intent radiation therapy (RT). The T-stages according to the 1987 UICC classification were: 26 T1, 141 T2, 104 T3, and 34 T4. There were 49 pts with nodal involvement at presentation. Pretreatment anal function scoring according to our in-house system was: 22 scored 0, 182 scored 1, 74 scored 2, 7 scored 3, 11 scored 4, and 9 not available pts. The treatment started with external beam RT (EBRT) in 303 pts (median dose: 45 Gy). After a rest period of 4 to 6 weeks, a boost of 20 Gy was delivered by EBRT in 279 pts and by interstitial 192Ir brachytherapy (Bcy) in 17 pts. Seven pts received only one course of EBRT (mean dose: 49.5 Gy) and 2 pts were treated with interstitial 192Ir Bcy alone (55 and 60 Gy, respectively). Concomitant chemotherapy (5-fluoro-uracil and either mitomycin C or cisplatin) was delivered to 19 pts. Mean follow-up was 103 months., Results: At the end of RT local tumor clinical complete response (cCR) rate was 80%. Out of 61 non responders or local progressive tumors 27 (44%) were salvaged with abdominoperineal resection (APR). The rate of local tumor relapse (LR) was 12%. Out of 37 LTR, 20 (54%) were salvaged with APR and one with interstitial 192Ir Bcy. The orevall local tumor control (LC) rate with or without salvage local treatment was 84%. LC rate with a good anal function scoring (score 0 and 1) was 56.5%. Among 181/186 available pts who preserved their anus, 94% had a good anal function scoring. For a subgroup of 15 pts with length tumor <2 cm-N0, the LC rate after the end of RT was 100%, the LC rate with or without local salvage treatment was 100%, and among 13 available pts who preserved their anus, the anal function scoring was good in 12 pts (92%). The 10-years disease-free survival was 74%. After multivariate analysis, 3 independent predicting factors significantly influenced the disease-free survival: gap duration between 2 courses of RT (>38 days vs < or =38 days, P =0.0025), pretreatment anal function scoring (0 vs 1 vs 2 vs 3 vs 4, P =4.4 10(-6)), and cCR after the end of RT (no complete response vs complete response, P =2.5 10(-14))., Conclusion: We confirm excellent results with RT in T1 and T2 lesions. However, chemoradiotherapy should be prefered to improve survival free of colostomy with a good anal sphincter function for tumors more than or equal to 2 cm in length and locally advanced tumors.

Purpose: To evaluate our data concerning the prognostic factors for locoregional control, survival, late complications, and sphincter conservation in a series of epidermoid cancers of the anal canal without clinical evidence of metastasis., Methods and Materials: Between June 1972 and January 1997, 305 patients were treated with curative-intent radiotherapy (RT). The T stage according to the 1987 International Union Against Cancer classification was T1 in 26, T2 in 141, T3 in 104, and T4 in 34. Forty-nine patients had nodal involvement at presentation. The pretreatment anal function score, according to our in-house system, was 0 for 22 patients, 1 for 182, 2 for 74, 3 for 7, and 4 for 11 patients; for 9 patients, scores were unavailable. The treatment started with external beam radiotherapy (EBRT) in 303 patients (median dose 45 Gy). After a rest period of 4-6 weeks, a boost of 20 Gy was delivered by EBRT in 279 patients and by interstitial (192)Ir brachytherapy in 17 patients. Seven patients received only one course of EBRT (mean dose 49.5 Gy), and 2 patients were treated with interstitial (192)Ir brachytherapy alone (55 Gy and 60 Gy). Concomitant chemotherapy (5-fluorouracil and either mitomycin C or cisplatin) was delivered to 19 patients. The mean follow-up was 103 months (median 84)., Results: At the end of RT, the local tumor clinical complete response rate was 96% for T1, 87% for T2, 79% for T3, and 44% for T4. Of the 61 locally progressive tumors, 27 (44%) were salvaged with abdominoperineal resection. The rate of local tumor relapse was 12%. Among 37 local tumor relapses, 20 (54%) were salvaged with abdominoperineal resection and one with interstitial (192)Ir brachytherapy. The overall local control rate (with or without salvage local therapy) was 84%. The local control rate with good anal function (score 0 or 1) was 56.5%. Of 181 available patients with their anus preserved, 94% had good anal function. For a subgroup of 15 patients with a tumor length of <2 cm and without nodal involvement, the clinical complete response rate after RT completion was 100%, the local control rate with or without local salvage treatment was 100%, and among 13 available patients with their anus preserved, the anal function score was good in 12 patients (92%). The 10-year disease-free survival rate was 74%. After multivariate analysis, three independent predictive factors significantly influenced disease-free survival: the interval between the two courses of RT (>38 days vs. < or =38 days, p = 0.0025), pretreatment anal function score (0 vs. 1 vs. 2 vs. 3 vs. 4, p = 4.4.10(-6)), and clinical complete response after RT completion (no complete response vs. complete response, p = 2.5.10(-14))., Conclusion: We confirm the excellent results with RT in T1 and T2 lesions. However, to improve survival without colostomy with good anal sphincter function, chemoradiotherapy should be preferred for tumors > or =2 cm in length and for locally advanced tumors.

Purpose: To evaluate repeat radiosurgery (RS2) for cerebral arteriovenous malformations (AVMs) after failure of initial radiosurgery (RS1)., Methods and Materials: Between 1986 and 2000, 41 patients underwent RS2. Nine patients were not assessable: seven had insufficient follow-up (RS2 in 1999 and 2000) and two had no recent control angiography data. Thus, 32 (78%) of 41 patients were assessed. Most lesions (29 [90%] of 32) were supratentorial: 22 (69%) on the left, 8 (25%) on the right, and 2 on the midline (6%). The patients had Spetzler-Martin Grade 1-5 (median Grade 3). The symptoms before RS1 included hemorrhage in 20 (63%), epilepsy in 10 (31%), progressive neurologic deficits in 2 (6%), and headaches in 6 (19%). Five patients had two or more symptoms. Twenty-two patients (69%) had received other treatment before RS1, including neurosurgery in 3 patients (9%) and one to six embolizations in 19 patients. At RS1, the median largest nidus dimension was 2.7 cm (range 0.8-5). The median volume was 2.7 cm(3) (range 1.2-9.9). The median time from RS1 to RS2 was 52 months (range 12-126). Between RS1 and RS2, 7 (22%) of 32 patients experienced bleeding. The same irradiation technique was used for RS1 and RS2, except for 2 patients who underwent RS2 at another institution. Circular 15-MV X-ray minibeams (range 6-20 mm) and coronal arcs were used. RS1 was monoisocentric in 75% of cases and multiisocentric in 25%. At RS2, the median largest nidus dimension was 3 cm (range 1.4-5). The median volume was 4.2 cm(3) (range 0.8-13.4). RS2 was monocentric in 72% of cases and multiisocentric in 28%. After RS2, the median follow-up was 19.5 months (range 0-79; mean 25.3)., Results: After RS2, the obliteration rate was 59.3% (19 of 32). The median time to arteriographic obliteration was 21 months (range 12-96). The survival rate was 97% (31 of 32). Five of the 13 patients with a nonobliterated nidus experienced complications; 3 had bleeding (9%) and 2 without prior neurologic deficits developed partially regressive neurologic deficits. One patient with a previously existing deficit developed an additional new partially regressive neurologic deficit after an episode of bleeding. Thus, 3 (9%) of 32 patients had neurologic complications. Moderate-grade parenchymal changes at MRI increased after RS2 (88.2% vs. 57.7% after RS1; p = 0.10, not significant). However, necrosis-like changes did not significantly increase. After RS1 failure, salvage may be attempted by embolization, neurosurgery, or RS2. RS2 should be considered after the second successive annual angiogram if reduction of the nidus is <25%., Conclusion: The results after RS2 are encouraging. A multidisciplinary approach is mandatory to reduce the initial failure rate and to choose the modality and timing of salvage treatment.

Purpose: To evaluate our data concerning prognostic factors and treatment toxicity in a series of operable cervical carcinomas., Methods and Materials: Between May 1972 and January 1994, 414 patients with cervical carcinoma, staged according to the 1995 FIGO staging system (286 Stage IB1, 38 Stage IB2, 56 Stage IIA, and 34 Stage IIB with 1/3 proximal parametrial involvement), underwent radical hysterectomy with (n = 380) or without (n = 34) bilateral pelvic lymph node dissection (N+: n = 68). Group I included 168 patients who received postoperative radiation therapy (RT): 64 patients had low-dose-rate vaginal brachytherapy with a median total dose (MTD) of 50 Gy; 93 patients had external beam pelvic RT (EBPRT) with an MTD of 45 Gy over 5 weeks, followed by low-dose-rate vaginal brachytherapy (MTD: 20 Gy); and 11 patients had EBPRT alone (MTD: 50 Gy over 6 weeks). Group II included 246 patients treated with preoperative low-dose-rate uterovaginal brachytherapy (MTD: 65 Gy); 32 of these 246 patients also received postoperative EBPRT (MTD: 45 Gy over 5 weeks) delivered to the parametria and pelvic nodes. Mean follow-up from the beginning of treatment was 106 months., Results: First events included isolated locoregional recurrences (35 patients), isolated distant metastases (27 patients), and locoregional recurrences with synchronous metastases (13 patients). The 10-year disease-free survival (DFS) rate was 88% for Stage IB1, 44% for Stage IB2, 65% for Stage IIA, and 48% for Stage IIB. Multivariate analysis showed that independent factors influencing the probability of DFS were as follows: cervical site (exocervical or endocervical vs. both endo- and exocervical, relative risk [RR]: 1.77, p = 0.047), vascular space invasion (no vs. yes, RR: 1.95, p = 0.041), age (>51 years vs. 1 cm: 83% vs. 41%, respectively, p = 0.001). The overall postoperative complication rate was 10% in Group I and 9% in Group II (p = 0.7). The rate of postoperative ureteral complications requiring surgical intervention was lower in Group I than in Group II (0.6% vs. 2.3%, respectively, p = 0.03). The overall 10-year rate for Grade 3 and 4 late radiation complications was 10.4%. Postoperative EBPRT significantly increased the 10-year rate for Grade 3 and 4 late radiation complications (yes vs. no: 22% vs. 7%, respectively, p = 0.0002)., Conclusion: The prognosis for patients with cervical carcinoma was not influenced by the sequence of adjuvant RT (preoperative uterovaginal brachytherapy vs. postoperative RT) for Stages IB, IIA, and IIB with 1/3 proximal parametrial involvement. However, postoperative EBPRT increased the risk of late radiation complications.

Purpose: To identify prognostic factors and treatment toxicity in a series of operable stages IB and II cervical carcinomas., Patients and Methods: Between May 1972 and January 1994, 414 patients (pts) with cervical carcinoma staged according to the 1995 FIGO staging system underwent radical hysterectomy with (n = 380) or without (n = 34) bilateral pelvic lymph node dissection. Lateral ovarian transposition to preserve ovarian function was performed on 12 pts. The methods of radiation therapy (RT) were not randomised and depended on the usual practices of the surgical teams. Group I: 168 pts received postoperative RT (64 pts received vaginal brachytherapy alone [mean total dose (MD): 50 Gy], 93 pts had external beam pelvis RT (EBPRT) [MD: 45 Gy over 5 weeks] followed by vaginal brachytherapy [MD: 20 Gy], and 11 pts had EBPRT alone [MD: 50 Gy over 6 weeks]. Group II: 246 pts received preoperative utero-vaginal brachytherapy [MD: 65 Gy], and 32 of theses 246 pts also received postoperative EBPRT [MD: 45 Gy over 5 weeks] delivered to the parametric and the pelvic lymph nodes with a midline pelvic shield. The mean follow-up was 106 months., Results: The 10-year disease-free survival (DFS) rate was 80%. From 75 recurrences, 35 were isolated locoregional. Multivariate analysis showed that independent factors decreasing the probability of DFS were: both exo and endocervical tumour site (p = 0.047), lymph-vascular space invasion (p = 0.041), age < or = 51 yr (p = 0.013), 1995 FIGO staging system (stage IB1 vs stage IIA, p = 0.004, stage IB1 vs stage IB2, p = 0.0009, and stage IB1 vs stage IIB with 1/3 proximal parametrical infiltration, p = 0.00002), and histological pelvic involved lymph nodes (p = 0.00009). Methods of adjuvant RT did not influence the probability of DFS (group I vs group II, p = 0.10). The postoperative complication rate was 10.2% in group I and 8.9% in group II (p = 0.7) but the postoperative urethral complication rate necessitating surgical intervention with reimplantation was lower in group I than in group II (0.6% vs 2.3%, respectively, p = 0.03). The 10-year rate for grade 3 and 4 late radiation complications according to the LENT-SOMA scoring system was 10.4%. EPRT significantly increased the 10-year rate for grade 3 and 4 late radiation complications (yes vs no: 22% vs 7%, respectively, p = 0.0002)., Conclusion: In our series, the methods of adjuvant RT (primary surgery vs preoperative uterovaginal brachytherapy) do not seem to influence the prognosis of the stage IB, IIA, and IIB (with 1/3 proximal parametrical involvement only) cervical carcinomas. The postoperative EPRT applied according to histopathological risk factors after surgical treatment increases the risk of late radiation complications.

Purpose: To identify prognostic factors and treatment toxicity in a series of operable bulky stages I and II cervical carcinomas treated with a therapeutic modality combining primary irradiation and surgery., Patients and Methods: Between July 1982 and May 1996, 66 patients with bulky squamous-cell cervical carcinomas (stage IB2, IIA, and IIB with 1/3 proximal parametrial invasion) underwent primary external beam pelvic radiation therapy (37.40 Gy to 40 Gy over 4.5 weeks) and low-dose-rate uterovaginal brachytherapy (20 Gy) followed, 5 to 6 weeks later, by class II modified radical hysterectomy with bilateral pelvic lymphadenectomy. The four last patients received concomitant chemotherapy during the first and the fourth radiation week combining 5-FU and cisplatin. A clinical pelvic lymph node involvement had been observed in 7 patients. The clinical median tumor size was 5 cm in diameter (range: 4.5-8 cm). The median follow-up was 97 months., Results: Pathologic complete tumor response in specimen of hysterectomy were observed in 46 patients. Six patients had pathologic unilateral iliac lymph node involvement. The 5- and 10-year specific survival rates were 79 and 74%, respectively. The 5- and 10-year disease-free survival rates were 76% and 71%, respectively. The 10-year local control rate was 85%. The 10-year probability for pelvic recurrence was significantly influenced by the pathologic tumor response: 26% in the residual group vs 5% in the complete tumor response group, P = 0.024). After multivariate analysis, the independent factors decreasing the probability of disease-free survival were: pathologic pelvic lymph node involvement (P = 0.029), and parametrial invasion (P = 0.031). Five late severe complications requiring surgical intervention were observed: 2 bowel obstructions, 1 ureteral stenosis, 1 vesicovaginal fistula, and 1 radiation induced unilateral femoral necrosis., Conclusion: A good local control is obtained after combined primary radiation therapy and surgery for bulky stages I and II cervical carcinomas. In our more recent practice, the treatment combines primary concomitant chemoradiation followed by surgery including pelvic and para-aortic lymphadenectomy.

Purpose: Uterine sarcoma is a rare disease and survival is poor. From 1975 to 1995, 73 uterine sarcomas were treated at the Curie Institute, and we analysed prognostics factors of survival., Patients and Methods: Seventy-one patients underwent primary surgery, in most cases a radical non conservative surgery and a lymphadenectomy. Every patient had an irradiation (external beam irradiation and/or brachytherapy), and 24 patients received adjuvant chemotherapy. We observed that youngest patients had more leiomyosarcomas and low histologic grade tumours. Median survival was 42 months, and 5-years survival and local control were 36 and 68% respectively. Pelvic recurrences were most often before 2 years. This series demonstrates the impact of adjuvant irradiation on local control. This impact was stronger if the tumour had a high histologic grade (p < 0.01). However, irradiation, as well as chemotherapy, had no impact on the survival., Conclusion: The study confirmed that irradiation enable a better local control. However modalities of radiation therapy (brachytherapy and/or external beam radiotherapy, dose, volume), are still controversed.

Purpose: To identify prognostic factors and treatment toxicity in a series of operable endometrial adenocarcinomas., Patients and Methods: Between November 1971 and October 1992, 437 patients (pts) with endometrial carcinoma, staged according to the 1988 FIGO staging system, underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy without (n = 140) or with (n = 297) pelvic lymph node dissection. The chronology of RT was not randomized and depended on the usual practices of the surgical teams. Group I: 79 pts received preoperative uterovaginal brachytherapy (mean total dose [MD]: 57 Gy). Group II: 358 pts received postoperative RT (196 pts received vaginal brachytherapy alone [MD: 50 Gy], 158 pts had external beam pelvis RT [EPRT] [MD: 46 Gy over 5 weeks] followed by vaginal brachytherapy [MD: 17 Gy], and 4 pts had EPRT alone [MD: 46 Gy over 5 weeks]). The mean follow-up was 128 months., Results: The 10-year disease-free survival rate was 86%. From 57 recurrences, 12 were isolated locoregionally. Multivariate analysis showed that independent factors decreasing the probability of disease-free survival were: histologic type (clear cell carcinoma, p = 0.038), largest histologic tumor diameter > 3 cm (p = 0.015), histologic grade (p = 0.008), myometrial invasion > 1/2 (p = 0.0055), and 1988 FIGO staging system (p = 9.10(-8)). In group II, the addition of EPRT did not seem to improve locoregional control. The postoperative complication rate was 7%. The independent factors increasing the risk of postoperative complications were FIGO stage (p = 0.02) and pelvic lymph node dissection (p = 0.011). The 10-year rate for grade 3 and 4 late radiation complications according to the LENT-SOMA scoring system was 3.1%. EPRT independently increased the 10-year rate for grade 3 and 4 late radiation complications (R.R.: 5.6, p = 0.0096)., Conclusion: EPRT increases the risk of late radiation complications. After surgical and histopathologic staging with pelvic lymph node dissection, in a subgroup of intermediate risk patients (stage IA grade 3, IB-C and II), postoperative vaginal brachytherapy alone is probably sufficient to obtain a good therapeutic index. Results for patients with stage III tumor are not satisfactory.

Purpose: To evaluate, qualitatively and quantitatively, the role of surgical clips in planning the tumor bed electron or brachytherapy boost in patients undergoing breast-conserving surgery and radiotherapy., Patients and Methods: In 60 patients with breast cancer stage I or II, the excision cavity boundaries were marked by clips at surgery. Patients received a boost with brachytherapy (n = 51) or electron beam (n = 9) after whole breast irradiation. The boost target volume was first planned using clinical, mammography and operative information and its accuracy evaluated by screening the surgical clips and, if necessary, adjusting the field to encompass all clips and to include the scar. Dosimetry was retrospectively performed for each brachytherapy patient and for each surgical clip., Results: It was necessary to modify the target volume field in 11 cases (18%). The average dose received by the surgical clips was 116.1% of the dose delivered to the reference isodose (median: 101.75%, range: 16-457%). However, dose heterogeneity was important in the same patient and between patients., Conclusion: Delineation of the boost target volume with surgical clips is more accurate than with clinical landmarks alone but this technique does not allow measurements of the clip-chest wall and clip-skin distances. Virtual simulation with CT-scan cuts is recommended for optimising boost planning.

Background and Purpose: Between 20 to 50% of cerebral arteriovenous malformations treated with radiosurgery (RS) fail to obliterate 2 to 5 years after irradiation. Patients are not protected against the risks leading to treatment. Two therapeutic options can be used to eradicate the persisting nidus: micro-surgery and a second irradiation. Our group has reirradiated 39 such patients., Material: From 1989 to 2000, 39 patients have been reirradiated (14 females and 25 males; median age 31 years). There were more left lesions: 59% than right (35%) and 5% on midline. The most frequent locations were: temporal 12 cases; parietal 8 cases; frontal 7 cases; thalamus 7 cases. The predominant first symptoms were hemorrhage (68.5%) and seizure (15.8%). Prior RS, 21/39 patients had embolization (53.8%) and 3 surgery. Method. Treatment has been performed with the same system for the first and the second radiosurgery for 37 patients. Planification and dosimetry improved during that period. The level of dose was similar for the 2 RS. MRI has been used as a non invasive follow-up tool., Results: Only 28 patients were evaluable because 7/39 patients had the second radiosurgery in 1999 or in 2000 and data were lacking at the time of writing for 4 patients. Obliteration rate was 17/28 (60.7%). Nine patients bled between the two radiosurgery procedures., Complications: 4 new regressive deficits occurred after the second radiosurgery. The rate of parenchymal changes were higher, after the second radiosurgery. Except one patient who died of a non-related affection 2 years after obliteration of his cerebral arteriovenous malformation, thus 38/39 patients were alive., Conclusion: This series was small compared to the potential number of candidates suffering from failure of the first radiosurgery, but the results are promising.

Purpose: To identify prognostic factors and treatment toxicity in a series of operable endometrial adenocarcinomas., Methods and Materials: Between November 1971 and October 1992, 437 patients (pts) with endometrial carcinoma, staged according to the 1988 FIGO staging system (225 Stage IB, 107 Stage IC, 4 Stage IIA, 35 Stage IIB, 30 Stage IIIA, 6 Stage IIIB, and 30 Stage IIIC), underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy without (n = 140) or with (n = 297) pelvic lymph node dissection. The chronology of adjuvant RT was not randomized and depended on the usual practices of the surgical teams. Seventy-nine pts (Group I) received preoperative low-dose-rate uterovaginal brachytherapy (mean dose [MD]: 57 Gy). Three hundred fifty-eight pts (Group II) received postoperative RT. One hundred ninety-six pts received low-dose-rate vaginal brachytherapy alone (MD: 50 Gy). One hundred fifty-eight pts had external beam pelvic RT (MD: 46 Gy) followed by low-dose-rate vaginal brachytherapy (MD: 17 Gy). Four pts had external beam pelvic RT alone (MD: 47 Gy). The mean follow-up from the beginning of treatment was 128 months., Results: The 10-year disease-free survival rate was 86%. From 57 recurrences, only 12 were isolated locoregional recurrences. The independent factors decreasing the probability of disease-free survival were as follows: histologic type (clear-cell carcinoma, p = 0.038), largest histologic tumor diameter >3 cm (p = 0.015), histologic grade (p = 0.008), myometrial invasion > 1/2 (p = 0.005), and 1988 FIGO staging system (p = 9.10(-8)). In Group II, the addition of external beam pelvic RT did not seem to independently improve vaginal or pelvic control. The postoperative complication rate was 7%. The independent factors increasing the risk of postoperative complications were stage FIGO (p = 0.02) and pelvic lymph node dissection (p = 0.011). The 10-year rate for Grade 3 and 4 late radiation complications according to the LENT-SOMA scoring system was 3.1%. External beam pelvic RT independently increased the rate for Grade 3 and 4 late complication (RR: 5.6, p = 0.0096)., Conclusion: Postoperative external beam pelvic RT increases the risk of late radiation complications. After surgical and histopathologic staging with pelvic lymph node dissection, in subgroup of "intermediate-risk" patients (Stage IA Grade 3, IB-C and II), postoperative vaginal brachytherapy alone is probably sufficient to obtain a good therapeutic index. Results for patients with Stage III tumor are not satisfactory.

Purpose: To validate a computed tomography (CT) and (18)F-deoxyglucose (FDG) image fusion procedure and to evaluate its usefulness to facilitate target definition and treatment planning in three-dimensional conformal radiation therapy (3D-CRT) for non-small-cell lung cancer., Methods and Materials: Twelve patients were assessed by CT and FDG-coincidence mode dual-head gamma camera (CDET) before radiotherapy. The patients were placed in a similar position during CT and FDG-CDET. Matching was achieved by minimizing the cost function by 3D translation and rotation between four landmarks drawn on the patient's skin. Virtual simulation was performed from image fusion and estimated dose-volume histograms (DVH) were calculated., Results: Quantitative analysis indicated that the matching error was < 5 mm. Fusion of anatomic and metabolic data corrected staging of lymph nodes (N) for 4 patients and staging of metastases for 1 patient. In these 5 patients, DVH revealed that the lung volume irradiated at 20 Gy (Vl(20)) was decreased by an average of 22.8%, and tumor volume irradiated at the 95% isodose (V(95)) was increased by 22% and 8% for 2 patients, respectively, and was decreased by an average of 59% for 3 patients after fusion. No difference in terms of Vl(20) and V(95) was observed for the other 7 patients., Conclusion: We have validated CT and FDG-CDET lung image fusion to facilitate determination of lung cancer volumes, which improved the accuracy of 3D-CRT.

Postoperative external radiation in non-small-cell lung cancer has remained a topic of debate since the first randomized study examining the potential contribution of postoperative radiotherapy published more than 35 years ago and despite a recent meta-analysis published in 1998 that included 9 randomized prospective studies. Among the 4 eligible randomized studies including non-small-cell lung cancer patients in complete remission of stage II (N1) disease, none demonstrated a significant advantage on survival. In addition, some of these studies disclosed an apparently deleterious effect after postoperative radiotherpy. Although the modalities and the technical quality of radiotherapy and surgical resection were different for the different studies or within a given study, or in some of the older studies even obsolete, and although the precision of the outcome evaluation can be criticized, there is currently no argument for proposing postoperative radiotherapy as a routine systematic practice with conventional methods of bidimensional dosimetric planification after complete surgical resection with good quality mediastinal node dissection for non-small-cell lung cancer patients with stage II (N1) disease. However, the contribution of postoperative radiotherpy with sufficient means for performing tridimensional conformational radiotherapy with individual optimization of computerized dosimetric planification taking into account the residual respiratory function after surgery remains to be evaluated in randomized prospective studies with rigorous control of the technical quality of the surgical resection and the radiotherapy and a precise statistical analysis of the locoregional and distant events in case of incomplete surgical resection and in more advanced stage disease (parietal T3, N0, stage III N2).