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Purpose. – To identify predicting factors of local control and survival after isolate local failure by statistical analysis of the data after breast-conserving treatment for early breast cancer.Methods and Patients. – In time of local failure, mean age was 54.7 years old , mean tumor size was 19.3 mm and recurrence was more often infiltrating ductal carcinoma (88%). Local recurrence was unifocal in 44 cases and localised outside of the site of the primary tumorectomy in 35 cases. Local failure treatment was a radical mastectomy or parietectomy (53 patients). Hormonotherapy was delivered in 36 patients and chemotherapy was delivered in 26 patients. Mean follow-up was 62 months.Results. – Fifteen patients developed second local recurrence in a mean time of 36 months. Five years local control rate was 68% after the first local failure. Surgery treatment (non-conservative surgery vs. conservative surgery) was the only factor which influenced local control. Six patients developed homolateral axillary and/or supraclavicular node recurrence. Twelve patients underwent metastasis in a mean time of 36 months after the first local recurrence. Five years metastasis free survival rate was 80%. Peritumoral vascular invasion in time of the first local failure increased metastasis risk and node recurrence. Second local failure did not alter metastasis free survival.Conclusion. – Peritumoral vascular invasion in time of the first local failure decreased node and metastasis free survival. Surgery should be radical, but the place of chemotherapy and hormonotherapy was not definite. [Copyright &y& Elsevier]

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 ≤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. [Copyright &y& Elsevier]

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]

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 ≤ 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. [Copyright &y& Elsevier]

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 (stages 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 recquiring surgical intervention were observed: 2 bowell 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. [Copyright &y& Elsevier]

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.