The clinical practice and dosimetric outcome of the manual adaptive planning during definitive radiotherapy for cervical cancer.

PROPOSE: To evaluate the advantage of the manual adaptive plans comparing to the scheduled plans, and explored clinical factors predicting patients suitable for adaptive strategy. METHODS AND MATERIALS: Eighty two patients with weekly online cone-beam computed tomography (CBCT) were enrolled. The re-CT simulation was performed after 15 fractions and a manual adaptive plan was developed if a significant deviation of the planning target volume (PTV) was found. To evaluate the dosimetric benefit, D98, homogeneity index (HI) and conformity index (CI) for the planning target volume (PTV), as well as D2cc of the bowel, bladder, sigmoid and rectum were compared between manual adaptive plans and scheduled ones. The clinical factors influencing target motion during radiotherapy were analyzed by chi-square test and logistic regression analysis. RESULTS: The CI and HI of the manual adaptive plans were significantly superior to the scheduled ones (P = 0.0002, 0.003, respectively), demonstrating a better dose coverage of the target volume. Compared to the scheduled plans, D98 of the manual adaptive plans increased by 3.3% (P = 0.0002), the average of D2cc to the rectum, bladder decreased 0.358 Gy (P = 0.000034) and 0.240 Gy (P = 0.03), respectively. In addition, the chi-square test demonstrated that age, primary tumor volume, and parametrial infiltration were the clinical factors influencing target motion during radiotherapy. Multivariate analysis further identified the large tumor volume (≥ 50cm3, OR = 3.254, P = 0.039) and parametrial infiltration (OR = 3.376, P = 0.018) as the independent risk factors. CONCLUSION: We found the most significant organ motion happened after 15 fractions during treatment. The manual adaptive plans improved the dose coverage and decreased the OAR doses. Patients with bulky mass or with parametrial infiltration were highly suggested to adaptive strategy during definitive radiotherapy due to the significant organ motion.

A Novel Delivery System of RGD-HSA Loaded GEM/CUR Nanoparticles for the Treatment of Pancreatic Cancer Therapy.

Introduction: Pancreatic cancer is one of the most common malignant tumors and is characterized by high malignancy, occult incidence and poor prognosis. Traditional chemotherapy drugs have limited efficacy and strong side effects. Therefore, there is an urgent need for a better treatment of the malignancy. Methods: The prepared arginine glycine peptide (RGD)-human serum albumin (HSA)-Gemcitabine (GEM)/Curcumin (CUR) nanoparticles (NPs) were characterized for physicochemical properties, stability and in vitro release. Comparisons of HSA-GEM/CUR NPs and RGD-HSA-GEM/CUR NPs regarding tissue distributions and pharmacodynamics were also carried out using mice as the animal models. Results: Transmission electron micrographs showed that RGD peptide-conjugated HSA-NPs had an irregular surface, good dispersion (PDI=0.139±0.03) and a uniform size distribution (Mean PS=115.6±5.7 nm). The ζ-potential was -17.3 mV. As regards in vitro release, non RGD modified NPs showed a faster release rate in 24 hours, yielding a release amount of 75% for GEM and 72% for CUR. RGD-HSA-GEM/CUR NPs exhibited 67% of accumulated release of GEM (63% for CUR) in 24 hours. This may be due to the HSA chain covering the surface of NPs, which hindered the drug release. The cytotoxicity of GEM/CUR co-loaded NPs was significantly higher than that of single-drug NPs (P < 0.05). In vivo study results indicated that RGD-HSA-GEM/CUR NPs had notable targeting effect on subcutaneous tumors, with a potential to actively deliver drugs to tumor tissues. Conclusion: In this study, we prepared RGD-HSA-GEM/CUR NPs that had both good water solubility and tumor-targeting property. The results also showed that the RGD modified NPs had advantages in increasing GEM/CUR concentration at tumor sites and reducing its distribution in peripheral organs.

The Case Selection for Vaginal Cuff Brachytherapy in Cervical Cancer Patients After Radical Hysterectomy and External Beam Radiation Therapy.

OBJECTIVE: To explore the suitable cases for vaginal cuff brachytherapy (VCB) combined with external beam radiation therapy (EBRT) in the postoperative treatment of cervical cancer. METHODS: We retrospectively analyzed the clinical data of 214 postoperative cervical cancer patients who received radiotherapy from January 2008 to December 2015. Among them, 146 patients received postoperative EBRT, 68 received EBRT plus VCB. There was no statistical difference in clinical and pathological characteristics between these two groups. Those who with negative vaginal cuff underwent supplemented 12-18 Gy/2-3 Fx VCB. Survival analyses were performed using Kaplan-Meier method, and Cox model was used to analyze prognostic factors. RESULTS: The median follow-up was 52 months (9-136 months), and 4-year RFS (recurrence-free survival) was 77%. Among them, 58 patients (27.10%) had local or distant recurrences, 29 (13.55%) in pelvis, six (2.80%) with metastases to para-aortic, 19 (8.88%) with distant metastases (including inguinal lymph nodes) and four (1.87%) with both local and distant recurrences. The postoperative brachytherapy boost did not improve RFS or OS (overall survival) among the investigated subjects, P = 0.77, P = 0.99, respectively. Neither it decreased the local relapse in the pelvis or vaginal cuff, P = 0.56, P = 0.59. Subgroup analyses showed that brachytherapy boost improved RFS in patients who had bulky mass (>4 cm) as well as 1) with deep stromal invasion (>50% stromal invasion), P = 0.012 or 2) received low EBRT dose (≤45 Gy), P = 0.033, and in patients with deep stromal invasion as well as received low EBRT dose (P = 0.018). CONCLUSIONS: We first proposed the case selection model for postoperative EBRT plus VCB. Brachytherapy boost were considered in the setting of postoperative radiotherapy if the patients had at least two out of these following factors: bulky mass, deep stromal invasion and low EBRT dose.

Lentiviral vector with a radiation-inducible promoter, carrying the ING4 gene, mediates radiosensitization controlled by radiotherapy in cervical cancer cells.

The presence of hypoxia in solid tumors is considered one of the major factors that contribute to radiation resistance. The aim of the present study was to establish a therapeutic system, which can be controlled by radiation itself, to enhance radiosensitivity. For this purpose, a lentiviral gene therapy vector containing the human inhibitor of growth 4 (ING4) and its upstream promoter, human early growth response factor-1 (EGR1), which possesses the radiation-inducible characteristics to activate the transcription of its downstream genes, was constructed. Downstream fluorescence proteins were investigated to ensure that the EGR1 promoter was induced by irradiation. Furthermore, ING4 open reading frame (ORF) expression was detected by western blotting. The cell cycle was analyzed by fluorescence-activated cell sorting analysis 48 h after the cells were exposed to X-rays ranging between 0 and 8 Gy. In cells stably and transiently transfected with reporter plasmids, the EGR1-driver gene was sensitive to ionizing irradiation. Furthermore, irradiation-induced ING4 gene expression was observed. The enhanced ING4 expression increased the number of cells in the G2/M phase and decreased the proportion of cells in the G1/S phase. Therefore, ING4 expression inhibited cell proliferation and was associated with less colonies being formed. Furthermore, ING4 suppressed hypoxia-inducible factor 1α expression under hypoxic conditions and promoted cell apoptosis. Overall, these results revealed that combining the EGR1 promoter and ING4 ORF using a lentivirus system may be a promising therapeutic strategy with which to enhance radiosensitivity controlled by radiation. However, further studies using in vivo models are required to confirm these findings.

Concurrent use of palbociclib and radiation therapy: single-centre experience and review of the literature.

Palbociclib in combination with endocrine therapy increases progression-free survival in patients with ER-positive, HER2-negative advanced breast cancer (BC). In this study, we retrospectively evaluated safety in the first patient treated with concurrent use of palbociclib and radiation therapy (RT) in the Curie Institute. Between April 2017 and August 2019, 30 women with metastatic BC received locoregional and/or symptomatic irradiation at a metastatic site concurrently with palbociclib. The most common acute toxicities were radiodermatitis and neutropenia. Palbociclib had to be discontinued during RT in three locally treated patients who developed grade 3 radiodermatitis and febrile neutropenia, grade 2 dysphagia and metastatic disease progression, respectively. After a follow-up of at least 6 months, none of the patients had late toxicity. Concomitant administration of palbociclib with RT was reasonably well tolerated in our series of 30 patients. More prospective data with longer follow-up are needed to confirm these results.

Role of nutritional status in the early postoperative prognosis of patients operated for retroperitoneal liposarcoma (RLS): A single center experience.

PURPOSE: To assess the nutritional status and its role in the outcome of patients operated for retroperitoneal liposarcoma (RLS). MATERIAL AND METHODS: Retrospective study on consecutive patients operated with en bloc compartment resection for primary or local recurrence of RLS between 2016 and 2017. Preoperative nutritional and laboratory assessment comprising serum albumin, serum transthyretin, orosomucoid, and CRP was systematically performed. The following preoperative parameters were analysed: weight, body mass index (BMI), significant weight loss (>5% in one month and/or >10% in 6 months), serum albumin, transthyretin, CRP, orosomucoid. PINI (prognostic inflammatory and nutritional index) was calculated. RESULTS: There were 40 patients operated for RLS: 22 women and 18 men with a median age of 61 years (34-90). Median tumour was 280 mm (80-530). Median preoperative BMI was 24.8 (18-42) and median postoperative BMI was 23 (17.8-44). Twenty-one patients (52.5%) were considered to be malnourished: 3 with biological signs of malnutrition and 18 with weight loss. Eleven (47.6%) in the group of malnourished patients and 4 (26.3%) in the group with satisfactory nutritional status developed postoperative complications (p = 0.042). A PINI score>1 was related to significantly longer hospitalisation time 21.8 days (10-58) in comparison with 14.9 [9-30] in patients with PINI < 1, p = 0.003. CONCLUSIONS: The malnourished patients with RLS experienced more postoperative complications and longer hospitalisation. Nutritional status and biological markers contribute to the global management of RLS with improved postoperative behaviour including fewer complications and shorter hospitalisation. A prospective larger study with longer follow-up is necessary to refine these results.

The use of helical tomotherapy in the treatment of early stage breast cancer: indications, tolerance, efficacy-a single center experience.

PURPOSE: to evaluate our experience in terms of local control, survival, adverse effects in patients treated by adjuvant helical tomotherapy (HT) for breast cancer (BC). RESULTS: We studied 179 consecutive patients with 194 treated breasts with adjuvant HT. Median follow-up was 38.1 months. Median age was 53 years. Chemotherapy was administered to 83% of patients. All 133 hormone receptor positive tumours received hormonal therapy. As concurrent treatment, apart from trastuzumab monotherapy, 6 patients received systemic therapy concomitant to RT. The HT was generally well tolerated with mostly grade 1 and 2 skin reactions and esophagitis. Only 3% grade III early skin reactions. At last follow-up, there were 2 local recurrences, 1 regional lymph node (LN) recurrence and 6 with metastatic progression. The 5-year progression-free survival was 90.5% (95% CI 84.2-97.3). MATERIALS AND METHODS: A retrospective study of all patients treated by HT between 2009 and 2015 was done. Patients excluded were those with: breast implants, advanced or metastatic BC, recurrent disease. All patients received breast+/-boost or chest wall irradiation and most received with LN irradiation. Dose constraints for organs at risk were defined using optimization scale developed in our Department. Evaluation of early and late toxicity was done using Common Terminology Adverse Criteria Events v.4.0. CONCLUSIONS: HT can be used for a well selected group of breast cancer as bilateral tumours, complex anatomy and target volumes where the conventional radiation therapy techniques cannot ensure an optimal dose distribution. Longer follow-up is necessary to confirm and validate these results.

Whole breast radiotherapy in the lateral isocentric lateral decubitus position: Long-term efficacy and toxicity results.

PURPOSE: To evaluate previously published whole breast radiotherapy (WBRT) using ILD (isocentring lateral decubitus) technique in terms of toxicity and efficacy. MATERIALS AND METHODS: From 2006 to 2010, 832 female patients with early-stage breast cancer (BC) treated by conservative surgery underwent 3D-conformal WBRT-ILD at Institut Curie. The acute toxicity of treatment was evaluated weekly and the late toxicity (6months and later after the treatment) was evaluated every 6months till the 5th year after the end of the radiotherapy using NCI CTC v3.0 scale. Dosimetric study was performed to analyse the mean cardiac dose and the mean homolateral and contralateral lung doses. RESULTS: The median follow up was 6.4years. The median age was 61.5years (range, 29-90), and median body mass index (BMI) was 26.3. Fifty one percent of the patients presented left sided BC and 49% right sided. Different type of fractions were used: 46.5% of pts.: 50 (breast)+16Gy (boost) in 33fractions (fr), in 17.9%-50Gy/25fr, in 26.1%-40/15fr or 41.6Gy/13fr and in 9.5%: 30Gy/5fr. Acute dermatitis was present in 93% with a median of apparition of 4weeks, and only 2,8% grade 3. In multivariate analysis, the cup size had significant influence (p=0.0004) and the fractionation had a significative influence (p=0.0001). In the all patients' population, 94.1% of cases had no skin toxicity at 1year. No cardiac or pulmonary toxicity was reported. The median overall survival had not been reached at the end of follow-up. We observed 36 (3.6%) recurrences, as following: 30 local (breast) recurrences, 4 lymph node (LN), and 2pts experiencing both. CONCLUSION: Whole breast radiotherapy in the lateral decubitus position provides excellent results in terms of local control and survival. ILD is well tolerated with very good acute toxicity profile. No cardiac or pulmonary toxicity were observed in this study. Longer follow-up is needed to confirm these results.

Patterns of loco regional failure in women with breast cancer treated by Postmastectomy Conformal Electron Beam Radiation Therapy (PMERT): Large scale single center experience.

PURPOSE: To evaluate loco regional control and describe the patterns of loco regional failure in women with breast cancer irradiated by a previously described post-mastectomy highly conformal electron beam radiotherapy technique. MATERIALS AND METHODS: We included all women irradiated by PMERT for non-metastatic breast cancer (BC) between 2007 and 2011 in our department. All cases of bilateral BC were excluded. All patients who experienced loco regional recurrence have been studied. Mapping patterns of regional recurrences was also performed and compared with the ESTRO and RTOG Guidelines of volume definition and delineation guidelines. RESULTS: Among the 796 women included, 10.1% were triple-negative (TN) and 18.8% were HER2-positive and 24.6% of them had received neoadjuvant chemotherapy (CT). Internal mammary chain (IMC), supraclavicular (Level IV), infraclavicular (Levels III and II) and axillary LN (Level I) were treated in 85.6%, 88.3%, 77.9% and 14.9% of cases, respectively. With a median follow-up of 64 months (range: 6-102), 5-year locoregional (RFS and OS were 90% (95% CI: 88.1-92.4) and 90.9% (95% CI: 88.9-93), respectively. Twenty-three patients (2.9%) presented locoregional recurrences. Most of them presented aggressive biological features with grade III tumors in 17 patients (74%) with high mitotic index in 16 cases (70%) and triple negative tumors in 12 (52%). Lymphovascular invasion (LVI) was observed in 11 cases (48%). In 14 cases the locoregional recurrences were diagnosed at the same time as the metastatic disease whereas 4 patients presented distant metastases secondarily. Local (Chest wall) recurrences occurred in 13 cases (56%) with the coverage by the isodose of 47.5 Gy (isodose 95%). Fifteen regional recurrences (lymph nodes) were observed in 13 patients. Only 3 regional recurrences occurred within irradiated volumes and 12 regional recurrences occurred outside irradiated areas. CONCLUSION: In presented series, the local recurrences were related mostly to the tumor biological aggressivity and radio resistance. Small number was caused by geographical miss. Further follow-up and careful registration of the recurrences is needed to improve their understanding.

Preliminary experience of the concurrent use of radiosurgery and T-DM1 for brain metastases in HER2-positive metastatic breast cancer.

This is preliminary study assessing the efficacy and safety of concurrent use of radiation therapy (RT) and T-DM1 for the treatment of brain metastases (BM) in patients with HER2-positive metastatic breast cancer (BC). We retrospectively studied 12 patients treated for BM at the Institut Curie in 2014-2015 with T-DM1 and concurrent (4) or sequential (8) radiosurgery with or without whole brain irradiation. The following variables were studied: local control, clinical and radiological response as well as early and late side effects. The mean age of the population was 38 years at the time of diagnosis of BC and 46 years at of BM. All patients were with good PS. The response rate of the concurrent treatment group was 75 % with 1 complete response, 1 partial response, one stable disease and 1 progression. Comparatively, the response rate in the sequential group was as follows: two complete responses, two partial responses, six cases of stable disease and two cases of local progression. No patient experienced interruption of irradiation because of side effects. About 50 % of patients were asymptomatic after treatment. Radiation necrosis was observed in 50 % of patients in the concurrent group and 28.6 % of patients in the sequential group with a similar rate of oedema in the two groups. We found that the combination of T-DM1 and radiosurgery was feasible but can increase the incidence of radiation necrosis. Larger prospective studies with longer follow-up are needed to more clearly evaluate this association.

[Evaluation of preoperative radiotherapy or chemoradiotherapy in sphincter preservation for locally advanced middle-low rectal cancer].

OBJECTIVE: To investigate the effect of preoperative radiotherapy or chemoradiotherapy on the sphincter preservation and local tumor control as well as survival for the patient with locally advanced middle-low rectal cancer. METHODS: 121 locally advanced middle-low rectal cancer patients were treated with preoperative radiotherapy or chemoradiotherapy followed by surgery after rest of 4 to 6 weeks. 103 of these patients who underwent radical surgery were finally included in this study. The irradiation regimen was: 40 Gy/4 - 5 weeks, whereas 57 of these 103 patients received concurrent chemotherapy of 5-Fu or Xeloda. Sphincter-preserving surgery was performed in 59 patients and abdominoperineal resection in 44 patients. The survival was estimated by Kaplan-Meier model, and the differences between groups were compared using Log rank test. Multivariate analysis was performed by Cox's model. RESULTS: Ten patients (9.7%) achieved a complete pathological response (pCR) to preoperative radiotherapy or chemoradiotherapy. The sphincter preservation rate was 57.3%. The 3-year overall survival (OS) and disease free survival (DFS) was 66.3% and 59.5%, respectively. Univariate analysis showed that pCR and postoperative pTNM stage were prognostic factors affecting survival, whereas, only pTNM stage was an independent prognostic factor (P = 0.003) by multivariate analysis. CONCLUSION: Neoadjuvant preoperative radiotherapy and chemoradiotherapy is effective in local tumor control and improving survival for locally advanced middle-low rectal cancer, which can raise the rate of sphincter-preserving surgery, and achieve comparable result to abdominoperineal resection.