Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 ...trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response. Three patients experience grade 3 dose-limiting toxicities. The pre-specified endpoints are met, and overall response rate is 93.8% 95%CI: 69.8-99.8% with a 2-year PFS of 75% 95% CI: 56.5-99.5%. Compared to patients with progressive disease (PD), progression-free (PF) subjects show a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3
T cells to PD-L1
tumor cells and of FOXP3
T cells to proliferating CD11c
myeloid cells. PF show higher baseline levels of PD-1 and ICOS-L on tumor-infiltrating EMRA CD4
T cells and tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression on TAMs, higher peripheral frequencies of proliferating Tregs at baseline and higher PD-1 levels at week 6 post-treatment initiation on CD4 and CD8 T cell subsets. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of locally advanced cervical cancer displaying pre-existing, adaptive immune activation is warranted.
Radiotherapy for head and neck squamous cell carcinomas (HNSCC) is associated with a substantial morbidity and inconsistent efficacy. Human papillomavirus (HPV)-positive status is recognized as a ...marker of increased radiosensitivity. Our goal was to identify molecular markers associated with benefit to radiotherapy in patients with HPV-negative disease.
Gene expression profiles from public repositories were downloaded for data mining. Training sets included 421 HPV-negative HNSCC tumors from The Cancer Genome Atlas (TCGA) and 32 HNSCC cell lines with available radiosensitivity data (GSE79368). A radioresistance (RadR) score was computed using the single sample Gene Set Enrichment Analysis tool. The validation sets included two panels of cell lines (NCI-60 and GSE21644) and HPV-negative HNSCC tumor datasets, including 44 (GSE6631), 82 (GSE39366), and 179 (GSE65858) patients, respectively. We finally performed an integrated analysis of the RadR score with known recurrent genomic alterations in HNSCC, patterns of protein expression, biological hallmarks, and patterns of drug sensitivity using TCGA and the E-MTAB-3610 dataset (659 pancancer cell lines, 140 drugs).
We identified 13 genes differentially expressed between tumor and normal head and neck mucosa that were associated with radioresistance in vitro and in patients. The 13-gene expression-based RadR score was associated with recurrence in patients treated with surgery and adjuvant radiotherapy but not with surgery alone. It was significantly different among different molecular subtypes of HPV-negative HNSCC and was significantly lower in the "atypical" molecular subtype. An integrated analysis of RadR score with genomic alterations, protein expression, biological hallmarks and patterns of drug sensitivity showed a significant association with CCND1 amplification, fibronectin expression, seven hallmarks (including epithelial-to-mesenchymal transition and unfolded protein response), and increased sensitivity to elesclomol, an HSP90 inhibitor.
Our study highlights the clinical relevance of the molecular classification of HNSCC and the RadR score to refine radiation strategies in HPV-negative disease.
Chemo-radiotherapy (CRT) is the standard treatment for non-metastatic anal squamous cell carcinomas (ASCC). Despite excellent results for T1-2 stages, relapses still occur in around 35% of locally ...advanced tumors. Recent strategies focus on treatment intensification, but could benefit from a better patient selection. Our goal was to assess the prognostic value of pre-therapeutic MRI radiomics on 2-year disease control (DC).
We retrospectively selected patients with non-metastatic ASCC treated at the CHU Bordeaux and in the French FFCD0904 multicentric trial. Radiomic features were extracted from T2-weighted pre-therapeutic MRI delineated sequences. After random division between training and testing sets on a 2:1 ratio, univariate and multivariate analysis were performed on the training cohort to select optimal features. The correlation with 2-year DC was assessed using logistic regression models, with AUC and accuracy as performance gauges, and the prediction of disease-free survival using Cox regression and Kaplan-Meier analysis.
A total of 82 patients were randomized in the training (
= 54) and testing sets (
= 28). At 2 years, 24 patients (29%) presented relapse. In the training set, two clinical (tumor size and CRT length) and two radiomic features (FirstOrder_Entropy and GLCM_JointEnergy) were associated with disease control in univariate analysis and included in the model. The clinical model was outperformed by the mixed (clinical and radiomic) model in both the training (AUC 0.758 versus 0.825, accuracy of 75.9% versus 87%) and testing (AUC 0.714 versus 0.898, accuracy of 78.6% versus 85.7%) sets, which led to distinctive high and low risk of disease relapse groups (HR 8.60,
= 0.005).
A mixed model with two clinical and two radiomic features was predictive of 2-year disease control after CRT and could contribute to identify high risk patients amenable to treatment intensification with view of personalized medicine.
•Is a dissection of patterns of recurrence, one of rare studies in the literature, very useful for the everyday practice.•Analysis of patterns of recurrence in chest wall irradiation.
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.
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.
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 64months (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 47.5Gy (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.
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.
To summarize the results of pelvic insufficiency fracture (PIF) incidence in patients with anal or gynaecological cancer treated by pelvic intensity-modulated radiation therapy (IMRT).
The clinical ...and morphological (CT and/or pelvic MRI) characteristics of patients treated by IMRT at our institution between 2007 and 2014 were analyzed. The global incidence of PIF after external beam radiotherapy and the impact of tumour site (gynaecological or anal cancer) were determined. A dosimetric study was then performed to compare patients with and without pelvic fracture.
341 patients were treated by IMRT for gynaecological or anal cancer between 2007 and 2014. 15 patients experienced at least 1 pelvic fracture after external beam radiotherapy, corresponding to an overall incidence of 4.4%. Age and menopausal status were correlated with an increased fracture risk (p = 0.0274 and p < 0.0001, respectively). The site of the primary tumour (gynaecological or anal canal) was not associated with an excess fracture risk. The median maximum dose received at the fracture site was 50.3 Gy (range: 40.8-68.4 Gy).
The incidence of pelvic fracture after IMRT is low, but is higher after the age of 50 and in patients who are postmenopausal. Pre-treatment evaluation of bone density by bone densitometry and phosphorus-calcium assessment could be useful prior to the management of these patients. Advances in knowledge: Pelvic fractures are a frequent complication after radiotherapy. The influence of IMRT and clinical characteristics were evaluated in this study.
To evaluate previously published whole breast radiotherapy (WBRT) using ILD (isocentring lateral decubitus) technique in terms of toxicity and efficacy.
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.
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.
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.
Triple-negative breast cancer (TNBC) cells are sensitive to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining PARP inhibitors with ...radiotherapy in patients with TNBC would enhance the biological effectiveness of the irradiation and improve locoregional control is unclear.
To assess the safety and tolerability of PARP inhibition with olaparib used concurrently with radiotherapy in patients with TNBC with residual disease after neoadjuvant chemotherapy.
This phase 1 prospective dose-escalation trial (Olaparib and Radiation Therapy for TNBC RadioPARP trial) using a time-to-event continual reassessment method was performed from September 2017 to November 2019, with follow-up until November 2021. Participants had an incomplete pathologic response after neoadjuvant chemotherapy or unresectable TNBC despite previous neoadjuvant chemotherapy, an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, and adequate organ functions.
Olaparib was administered orally in the form of tablets and given at increasing doses (50 mg, 100 mg, 150 mg, or 200 mg twice daily). Olaparib therapy was started 1 week before radiotherapy and was continued concomitantly with radiotherapy. After breast-conserving surgery, a total dose of 50.4 Gy was delivered to the whole breast, with a 63-Gy simultaneously integrated boost to the tumor bed for patients younger than 60 years. After radical mastectomy or for unresectable tumors despite neoadjuvant chemotherapy, a total dose of 50.0 Gy was delivered to the chest wall (after mastectomy) or to the whole breast (for unresectable tumors). Regional lymph node stations could be treated with a total dose of 50.0 Gy to 50.4 Gy in cases of node-positive disease.
Main outcomes were the safety and tolerability of PARP inhibition with radiotherapy for early-stage, high-risk TNBC. Secondary outcomes included overall survival (OS) and event-free survival (EFS).
Among the 24 patients included in the trial (100% female; median age, 46 years range, 25-74 years), no dose-limiting toxic effects were observed, and olaparib was escalated to 200 mg twice daily without reaching the maximum tolerated dose. No late treatment-related grade 3 or greater toxic effect was observed, and the maximum observed treatment-related toxic effects at the 2-year follow-up were grade 2 breast pain, fibrosis, and deformity in 1 patient (4.2%). Three-year OS and EFS were 83% (95% CI, 70%-100%) and 65% (95% CI, 48%-88%), respectively. Homologous recombination status was not associated with OS or EFS.
The findings of this phase 1 dose-escalation trial suggest that PARP inhibition with olaparib concurrently with radiotherapy for early-stage, high-risk TNBC is well tolerated and should continue to be evaluated in further clinical trials.
ClinicalTrials.gov Identifier: NCT03109080.
Helical tomotherapy (HT) is a new promising tool whose use remains to be studied. This work assesses its impact for local irradiation in terms of side effects, as well as tumour control in locally ...advanced (LABC) and metastatic breast cancer (MBC).
We retrospectively reviewed data of 66 patients with LABC and MBC. Patients received standard fractionated radiotherapy by HT, with or without concurrent systemic treatment.
The median age was 60 years (28-77). The median follow-up of the population was 35.9 months (10.6-95.8). For 91% of patients, HT was concomitant with systemic treatments. Three patients experienced grade 3 skin toxicity and all had concurrent 5FU-vinorelbine. One patient who was receiving concurrent treatment with trastuzumab-pertuzumab had a decreased left ventricular ejection fraction by 14%. No late cardiac or lung toxicity was observed. A clinical benefit was observed in 75% of cases. At 2 months after HT, we observed tumour regression in 7/8 patients, as following: 1 complete, 4 partial responses, and 2 stable disease. The median survival for MBC group was 64.4 months (42.6-65.8) and 21.1 (6.1-36.1) months for LABC.
This study suggests that the use of HT is well tolerated and feasible with a multimodal strategy that includes concurrent systemic treatments for patients with LABC and MBC. Advances in knowledge: The survival of LABC and MBC increases and new safe tools are needed to determine optimal strategies of treatment. To our knowledge, this is the first paper describing the use of HT for this population.
for localized T1N0 squamous cell carcinoma of the anus (SCCA) standard radiotherapy (RT) may result in overtreatment and alternative strategies are debated.
T1N0M0 SCCA treated between 2015 and 2020 ...by local excision (LE) or RT were analyzed from the French prospective FFCD ANABASE cohort. Treatment strategies, recurrence-free and colostomy-free survivals (RFS, CFS) and prognostic factors were reported.
among 1135 SCCA patients, 99 T1N0M0 were treated by LE(n = 17,17.2%), or RT (n = 82,82.8%) including RT alone (n = 65,79.2%) or chemo-RT (n = 17, 20.7%). Median follow-up was 27.2 months 0.03–54.44. Median tumor size were 11.4 mm 0.9–20 and 15.3 mm 2–20 in the LE and RT groups respectively. Mean RT tumor dose was 59.4 Gy 18–69.4 Gy. One patient in LE group and 9 in RT group had a pelvic recurrence, either local (60%), nodal (10%) or both (30%). RFS and CFS at 24 months were 92.2%95%CI,83.4–96.4 and 94.6%95%CI,86.1–98.0, at 36 months 88.1%95%CI,77.1–94.2 and 88.5%95%CI,77.0–94.5, in LE and RT group respectively, without any significative difference (HR = 0.57;95%CI,0.07–4.45;p = 0.60). By univariate analysis, male gender was the only prognostic factor(HR = 5.57;95%CI, 1.76–17.63; p = 0.004).
this cohort confirms the heterogeneity of T1N0M0 SCCA management, questioning the place of RT alone, reduced dose or RT volume, and the safety of LE.
Abstract Purpose To report the efficacy of Hydrosorb® versus control (water based spray) as topical treatment of grade 1–2 radiodermatitis in patients (pts) treated for early stage breast cancer (BC) ...with normo fractionated radiotherapy (RT). Patients and methods BC pts were randomized to receive either Hydrosorb® (A) or water based spray (B). The primary endpoint was local treatment failure defined as interruption of RT because of skin radiotoxicity or change of local care because of skin alteration. Secondary endpoints were: evaluation of skin colorimetry, pain, quality of life. Results Two-hundred seventy-eight pts were enrolled. There were 186 successfully treated pts. There were 60 “failures” in the Hydrosorb® arm, and 62 in the control arm ( p = 0.72), but mostly without interruption of the RT. Twenty-four pts stopped RT for local care. The average absolute reduction of colorimetric levels between day 28 and day 0 was 4 in the Hydrosorb®, and 4.2 in the water spray groups, respectively ( p = 0.36). Forty-eight patients in the Hydrosorb® arm had a VAS >2 versus 51 pts in the placebo arm, i.e. 34% and 38%, respectively ( p = 0.45). A significant reduction of pain was observed on D 7 and D 21 in the Hydrosorb® arm. Conclusions The present study showed no significant difference between Hydrosorb® and simple water spray in the treatment of acute radio-induced dermatitis even if there was a trend to an improvement in pain at the first weeks after the treatment. Systematic prevention measures and modern breast cancer radiotherapy techniques now allow excellent tolerability, but the place of topical treatment to optimize this tolerability has yet to be defined. It seems that the most important part of the skin care is the prevention of skin reactions using new adapted techniques, as well as strict hygiene.
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