Recommendations for Post-Operative RadioTherapy After Complete Resection of Thymoma-a French DELPHI Consensus Initiative.

INTRODUCTION: Thymomas are rare intrathoracic malignancies that can relapse after surgery. Whether or not Post-Operative RadioTherapy (PORT) should be delivered after surgery remains a major issue. RADIORYTHMIC is an ongoing, multicenter, randomized phase 3 trial addressing this question in patients with completely R0 resected Masaoka-Koga stage IIb/III thymoma. Experts in the field met to develop recommendations for PORT. METHODS: A scientific committee from the RYTHMIC network identified key issues regarding the modalities of PORT in completely resected thymoma. A DELPHI method was used to question 24 national experts, with 115 questions regarding the following: (1) imaging techniques, (2) clinical target volume (CTV) and margins, (3) dose constraints to organs at risk, (4) dose and fractionation, and (5) follow-up and records. Consensus was defined when opinions reached more than or equal to 80% agreement. RESULTS: We established the following recommendations: preoperative contrast-enhanced computed tomography (CT) scan is recommended (94% agreement); optimization of radiation delivery includes either a four-dimensional CT-based planning (82% agreement), a breath-holding inspiration breath-hold-based planning, or daily control CT imaging (81% agreement); imaging fusion based on cardiovascular structures of preoperative and planning CT scan is recommended (82% agreement); right coronary and left anterior descending coronary arteries should be delineated as cardiac substructures (88% agreement); rotational RCMI/volumetric modulated arc therapy is recommended (88% agreement); total dose is 50 Gy (81% agreement) with 1.8 to 2 Gy per fraction (94% agreement); cardiac evaluation and follow-up for patients with history of cardiovascular disease are recommended (88% agreement) with electrocardiogram and evaluation of left ventricular ejection fraction at 5 years and 10 years. CONCLUSION: This is the first consensus for PORT in thymoma. Implementation will help to harmonize practices.

The safety and efficacy of total mesorectal excision (TME) surgery following dose-escalation: Surgical outcomes from the organ preservation in early rectal adenocarcinoma (OPERA) trial, a European multicentre phase 3 randomised trial (NCT02505750).

AIM: Nonsurgical treatment with chemoradiotherapy for rectal cancer is gaining interest as it avoids total mesorectal excision (TME) surgery and stoma. The OPERA trial aims to evaluate whether dose escalation with contact X-ray brachytherapy (CXB) boost improves organ preservation compared to external beam radiotherapy (EBRT) boost. It has been suggested that dose escalation adversely affects surgical outcomes and therefore we report outcomes following TME in OPERA at 36 months. METHODS: OPERA is a European multicentre phase 3 trial (NCT02505750) which randomises patients with cT2-3a-b, cN0-1, M0 to EBCRT (45 Gy in 25 fractions over 5 weeks with oral capecitabine 825 mg/m2 ) followed by EBRT boost (9 Gy in 5 fractions over 5 days) versus EBCRT followed by CXB boost (90 Gy in 3 fractions over 4 weeks). Patients were assessed at 14, 20 and 24 weeks from the start of treatment. Watch and wait management was adopted for patients who achieved a clinical complete response (cCR) at 24 weeks following treatment. Either local excision (LE) or TME surgery was offered for residual disease or local regrowth, according to patient and surgeon preference. Surgical morbidity and mortality were recorded prospectively. RESULTS: Between July 2015 and June 2020, 148 patients were randomised of which 141 were evaluable in March 2022. At median follow-up of 38.2 months (range: 34.2-42.5), surgery was performed for 66 (47%) patients. A total of 27 (20%) patients had local excision and 39 (29%) had TME surgery, 22/39 (56%) underwent anterior resection and 17/39 (44%) underwent abdominoperineal excision of the rectum. The R0 resection rate was 87%. There were no deaths, and six patients (15%) had Clavien-Dindo IIIb complications. Whilst there was a statistically significant decrease in the TME rate following CXB boost (HR 0.38, 95% CI: 0.19-0.74, p = 0.00419) there was no difference in surgical outcomes between patients who received EBRT and CXB boost. CONCLUSION: Dose escalation can facilitate nonsurgical treatment for cT2-3 rectal cancer patients who are fit but wish to avoid TME surgery and stoma. If TME surgery is required, then it can be performed safely and effectively.

Neoadjuvant chemoradiotherapy with radiation dose escalation with contact x-ray brachytherapy boost or external beam radiotherapy boost for organ preservation in early cT2-cT3 rectal adenocarcinoma (OPERA): a phase 3, randomised controlled trial.

BACKGROUND: Organ preservation after reaching clinical complete response on neoadjuvant therapy is gaining interest for rectal cancers, although the role of radiation dose escalation is still not known. We aimed to determine whether a contact x-ray brachytherapy boost, following or preceding neoadjuvant chemoradiotherapy, increases the probability of 3-year organ preservation for patients with early rectal cancers. METHODS: OPERA was a multicentre, open-label, phase 3 randomised controlled trial done at 17 cancer centres that included operable patients, aged 18 years or older, with cT2, cT3a, or cT3b adenocarcinoma of low-mid rectum, tumours of less than 5 cm in diameter, and cN0 or cN1 smaller than 8 mm. All patients received neoadjuvant chemoradiotherapy and 45 Gy external beam radiotherapy in 25 fractions over 5 weeks with concurrent oral capecitabine (825 mg/m2 twice a day). Patients were randomly assigned (1:1) to receive a boost of external beam radiotherapy at 9 Gy in five fractions (group A) or a boost with contact x-ray brachytherapy (90 Gy in three fractions; group B). Randomisation was done centrally using an independent web-based system and stratified by trial centre, tumour classification (cT2 vs cT3a or cT3b), tumour distance from rectum (<6 cm from anal verge vs ≥6 cm), and tumour diameter (<3 cm vs ≥3 cm). Treatment in group B was stratified by tumour diameter, with the contact x-ray brachytherapy boost given before neoadjuvant chemoradiotherapy in patients with tumours smaller than 3 cm. The primary outcome was organ preservation at 3 years, analysed in the modified intention-to-treat population. This study was registered with ClinicalTrials.gov, NCT02505750, and is ongoing. FINDINGS: Between June 14, 2015, and June 26, 2020, 148 patients were assessed for eligibility and were randomly assigned to group A (n=74) or group B (n=74). Seven patients withdrew their consent (five in group A and two in group B). 141 patients were included in the primary efficacy analysis, including 69 assigned to group A (29 with tumours <3 cm in diameter and 40 with tumours ≥3 cm) and 72 assigned to group B (32 with tumours <3 cm and 40 with tumours ≥3 cm). After a median follow-up of 38·2 months (IQR 34·2-42·5), the 3-year organ preservation rate was 59% (95% CI 48-72) in group A versus 81% (72-91) in group B (hazard ratio [HR] 0·36, 95% CI 0·19-0·70; p=0·0026). For patients with tumours less than 3 cm in diameter, 3-year organ preservation rates were 63% (95% CI 47-84) in group A versus 97% (91-100) in group B (HR 0·07, 95% CI 0·01-0·57; p=0·012). For patients with tumours of 3 cm or larger, 3-year organ preservation rates were 55% (95% CI 41-74) in group A versus 68% (54-85) in group B (HR 0·54, 95% CI 0·26-1·10; p=0·11). 21 (30%) patients in group A and 30 (42%) in group B had an early grade 2-3 adverse event (p=1·0). The most common early grade 2-3 adverse events were proctitis (four [6%] in group A, nine [13%] in group B) and radiation dermatitis (seven [10%] in group A, two [3%] in group B). The main late side-effect was grade 1-2 rectal bleeding due to telangiectasia, which was more frequent in group B (37 [63%] of 59) than in group A (five [12%] of 43; p<0·0001) and subsided after 3 years. INTERPRETATION: Neoadjuvant chemoradiotherapy with a contact x-ray brachytherapy boost significantly improved the 3-year organ preservation rate, particularly for patients with tumours smaller than 3 cm who were treated with contact x-ray brachytherapy first, compared with neoadjuvant chemoradiotherapy with a boost via external beam radiotherapy. This approach could be discussed and offered to operable patients with early cT2-cT3 disease who are keen to avoid surgery and seek organ preservation. FUNDING: The French Programme Hospitalier de Recherche Cinique.

Locoregional relapses in the ACCORD 12/0405-PRODIGE 02 study: Dosimetric study and risk factors.

PURPOSE: The aim of this study is to correlate locoregional relapse with radiation therapy volumes in patients with rectal cancer treated with neoadjuvant chemoradiation in the ACCORD 12/0405-PRODIGE 02 trial. PATIENTS AND METHODS: We identified patients who had a locoregional relapse included in ACCORD 12's database. We studied their clinical, radiological, and dosimetric data to analyze the dose received by the area of relapse. RESULTS: 39 patients (6.5%) presented 54 locoregional relapses. Most of the relapses were in-field (n = 21, 39%) or marginal (n = 13, 24%) with only six out-of-field (11%), 14 could not be evaluated. Most of them happened in the anastomosis, the perirectal space, and the usual lymphatic drainage areas (presacral and posterior lateral lymph nodes). Only patients treated for a lower rectum adenocarcinoma had a relapse outside of the treated volume. 2 patients with T4 tumors extending into anterior pelvic organs had relapses in anterior lateral and external iliac lymph nodes. CONCLUSIONS: Lowering the upper limit of the treatment field for low rectal tumors increased the risk of out of the field recurrence. For very low tumors, including the inguinal lymph nodes in the treated volume should be considered. Recording locoregional involvement, treated volumes, and relapse areas in future prospective trials would be of paramount interest to refine delineation guidelines.

Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study.

BACKGROUND: The incidence of anal squamous cell carcinoma has been increasing markedly in the past few decades. Currently, there is no validated treatment for advanced-stage anal squamous cell carcinoma. Therefore, we aimed to validate the clinical activity and safety of docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma. METHODS: We did a multicentre, single-arm, phase 2 study. We recruited patients from 25 academic hospitals, cancer research centres, and community hospitals in France who were aged 18 years or older with histologically confirmed anal squamous cell carcinoma, with metastatic disease or with unresectable local recurrence; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and with at least one evaluable lesion according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Chemotherapy-naive patients received either six cycles of standard DCF (75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1 and 750 mg/m2 per day of fluorouracil for 5 days, every 3 weeks) or eight cycles of modified DCF (40 mg/m2 docetaxel and 40 mg/m2 cisplatin on day 1 and 1200 mg/m2 per day of fluorouracil for 2 days, every 2 weeks), which were administered intravenously. The choice between the standard versus modified regimens was recommended based on, but not limited to, age (≤75 years vs >75 years) and ECOG performance status (0 vs 1). The primary endpoint was investigator-assessed progression-free survival at 12 months from the first DCF cycle; for the primary endpoint to be met, at least 11 (17%) of 66 enrolled patients had to be alive without disease progression at 12 months. Efficacy and safety analyses were done in a modified intention-to-treat population, defined as all patients who were evaluable for progression at 12 months who received at least one cycle of DCF. This trial is registered at ClinicalTrials.gov, number NCT02402842, and the final results are presented here. FINDINGS: Between Sept 17, 2014, and Dec 7, 2016, we enrolled 69 patients. Of these patients, three did not receive DCF. Of the 66 patients who received treatment, 36 received the standard DCF regimen and 30 received modified DCF. The primary endpoint was met: 31 (47%) of 66 patients were alive and progression free at 12 months. 22 (61%) of 36 patients who received the standard DCF regimen and 18 (60%) of 30 patients who received the modified DCF regimen had disease progression at data cutoff. 46 (70%) of 66 patients had at least one grade 3-4 adverse event (30 [83%] of 36 in the standard DCF regimen and 16 [53%] of 30 in the modified DCF regimen). The most common grade 3-4 adverse events were neutropenia (15 [23%]; eight [22%] for standard DCF vs seven [23%] for modified DCF), diarrhoea (12 [18%]; nine [25%] vs three [10%]), asthenia (ten [15%]; eight [22%] vs two [7%]), anaemia (ten [15%]; six [17%] vs four [13%]), lymphopenia (eight [12%]; three [8%] vs five [17%]), mucositis (seven [11%]; seven [19%] vs none), and vomiting (seven [11%]; five [14%] vs two [7%]). No grade 4 non-haematological adverse events and febrile neutropenia were observed with modified DCF, whereas three (8%) grade 4 non-haematological adverse events and five (14%) cases of febrile neutropenia were reported with standard DCF. 97 serious adverse events were reported (69 in patients who received the standard DCF regimen [61 drug-related] and 28 in those given the modified DCF regimen [14 drug-related]). No treatment-related deaths were recorded. INTERPRETATION: Compared with standard DCF, modified DCF provided long-lasting response with good tolerability in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma with ECOG performance status of 0-1 in the first-line setting, and therefore could be considered as a new standard of care for these patients. Regarding the elevated risk of high-grade and serious adverse events and febrile neutropenia, standard DCF cannot be recommended in this situation. FUNDING: Besançon University Hospital and Ligue contre le cancer Grand-Est.

Inaugural bone metastases in non-small cell lung cancer: a specific prognostic entity?

BACKGROUND: In non-small cell lung cancer patients (NSCLC), median survival from the time patients develop bone metastasis is classically described being inferior to 6 months. We investigated the subcategory of patients having an inaugural skeletal-related-event revealing NSCLC. The purpose of this study was to assess the impact of bone involvement on overall survival and to determine biological and tumoral prognosis factors on OS and PFS. An analysis of the subgroup of solitary bone metastasis patients was also performed. METHODS: In a population of 1208 lung cancer patients, 55 consecutive NSCLC patients revealed by inaugural bone metastasis and treated between 2003 and 2010, were retrospectively analysed. Survival was measured with a Kaplan-Meyer curve. Univariate and multivariate analysis were performed using the Stepwise Cox proportional hazard regression model. A p value of less than 0,05 was considered statistically significant. RESULTS: Estimated incidence of revealing bone metastasis is 4,5% among newly diagnosed lung cancer patients. Median duration of skeletal symptoms before diagnosis was 3 months and revealing bone site was located on axial skeleton in 70% of the cases. Histology was adenocarcinoma (78%), with small primary tumors Tx-T1-2 accounting for 71% of patients. Rate of second SRE is 37%.Median overall survival was 8.15 months, IQR [5-16 months], mean survival 13.4 months, and PFS was 3.5 months. In multivariate analysis, variables significantly associated with shortened survival were advanced T stage (HR=2.8; p=0.004), weight loss>10% (HR=3.1; p=0.02), inaugural spinal epidural metastasis (HR 2.5; p=0.0036), elevated C-reactive protein (HR=4.3; p=0.002) and TTF-1 status (HR=2.42; p=0.004). Inaugural spinal epidural metastasis is a very strong adverse pronostic factor in these cases, with a 3 months median survival. Single bone metastasis patients showed prolonged survival of 14.2 months versus 7.6 months, only in univariate analysis (HR=0.42; p=0.0059). CONCLUSION: Prognosis of lung cancer patients with inaugural SRE remains pejorative. Accurately estimating the survival of this population is helpful for bone surgical decision-making at diagnosis. The trend for a higher proportion of adenocarcinoma in NSCLC patients should result with an increasing number of patients with inaugural SRE at diagnosis.

The combination of the antiviral agent cidofovir and anti-EGFR antibody cetuximab exerts an antiproliferative effect on HPV-positive cervical cancer cell lines' in-vitro and in-vivo xenografts.

Cervical carcinoma remains a leading cause of female mortality worldwide and over 90% of these tumors contain the human papillomavirus (HPV) genome. Cross-talk between the epidermal growth factor receptor and HPV has been reported and is implicated in tumor progression. The combination of the antiviral compound cidofovir (Cd) with the monoclonal antibody antiepidermal growth factor receptor cetuximab (Cx) was evaluated. HPV-positive (HeLa and Me180) and HPV-negative (C33A, H460 and A549) human cancer cell lines were incubated with Cd (1-10 µg/ml) and/or Cx (10 or 50 µg/ml). The antitumor effect of the combination was assessed in vitro using a clonogenic survival assay, cell cycle analysis, and phospho-H2AX level. Tumor growth delay was assayed in vivo using xenograft models. A pan-genomic analysis was carried out to identify the genes expressed differentially in untreated HeLa HPV-positive cells versus cells treated by the Cd-Cx combination. The Cd-Cx combination inhibited proliferation in all the cell lines tested. The association of Cd and Cx exerted a synergistic activity on HPV-positive but not on HPV-negative cell lines. The combination delayed tumor growth of HPV-positive tumors in vivo; however, no efficacy was reported on HPV-negative C33A xenografts nor on cell lines treated by single-drug therapy. The combination induced an S-phase arrest associated with an enhanced level of the double-strand break in Me180 and HeLa cell lines. Gene profiling assays showed a significant differential modulation of genes in HeLa cell lines treated with the combination involving the EGR-1 transcription factor. The current data support a synergistic antiproliferative action of the Cd-Cx combination on HPV-related cervical tumors.

[Adjuvant and neoadjuvant treatment for pancreatic adenocarcinoma in 2006]. / Traitement adjuvant et néoadjuvant des adénocarcinomes pancréatiques en 2006.

About 5,300 new cases of pancreatic adenocarcinomas are diagnosed each year in France. At the time of diagnosis, an efficient carcinologic surgery will not be possible for nearly 80% of patients, in relation to locoregional extension or metastatic dissemination. After surgical resection, the median survival of resected patients ranges from 12 to 20 months, with a high rate of loco-regional or metastatic relapses. Numerous therapeutic trials, adjuvant or neo-adjuvant, have been conducted in aim of which to improve locoregioanl control and survival rates. Chemotherapy and chemoradiotherapy represent adjuvant treatments. In one trial, a chemotherapy regimen with 5-fluorouracil and folinic acid (FUFOL) has proven its efficience for survival improvement by comparison to chemoradiotherapy and is at this time the reference treatment in Europe. In another trial, using adjuvant gemcitabine results in an improvement in disease-free survival. Some phase III trials are in progress to evaluate new therapeutic strategies. The aim of neoadjuvant strategy using chemoradiotherapy is to enhance the rate of complete resections and by the way local control. This is under evaluation. This paper presents a summary of adjuvant and neoadjuvant trials for patients with potentially resectable pancreatic adenocarcinoma.