Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial.

BACKGROUND: The standard of care for the treatment of locally advanced rectal cancer results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free and metastatic-free survival with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival is reported here. PATIENTS AND METHODS: The study design, participants, and primary endpoint disease-free survival (DFS) have been reported for this multicenter, randomized, open-label, phase 3 trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on MRI, and staged cT3/T4. Key secondary endpoints included overall survival (OS), metastasis-free survival (MFS), and local and metastatic recurrence rate. RESULTS: With a median follow-up of 82.2 months, the 7-year DFS were 67.6% (95% CI 60.7%-73.9%) and 62.5% (95% CI 55.6%-68.6%) (RMST difference 5.73 months; 95% CI 0.05-11.41; p=0.048) in the neoadjuvant chemotherapy and the standard of care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0%-84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8%-77.8%) in the standard of care group (RMST difference 6.1 months; 95% CI 0.93-11.37; p=0.021). The 7-year OS was 81.9% (95% CI 75.8%-86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7-81.2) in the standard of care group (RMST difference 4.37 months; 95% CI 0.35-8.38; p=0.033). The safety profile remained unchanged since the previous analysis. CONCLUSION(S): Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed long-term DFS and MFS benefits in locally advanced rectal cancer patients and should be considered as a one of the best options of care for these patients.

Indication and perspectives of radiation therapy in the setting of de-novo metastatic prostate cancer.

Prostate cancer is the most common cancer and the third leading cause of cancer mortality in men. Each year, approximately 10% of prostate cancers are diagnosed metastatic at initial presentation. The standard treatment option for de-novo metastatic prostate cancer is androgen deprivation therapy with novel hormonal agent or with chemotherapy. Recently, PEACE-1 trial highlighted the benefit of triplet therapy resulting in the combination of androgen deprivation therapy combined with docetaxel and abiraterone. Radiotherapy can be proposed in a curative intent or to treat local symptomatic disease. Nowadays, radiotherapy of the primary disease is only recommended for de novo low-burden/low-volume metastatic prostate cancer, as defined in the CHAARTED criteria. However, studies on stereotactic radiotherapy on oligometastases have shown that this therapeutic approach is feasible and well tolerated. Prospective research currently focuses on the benefit of intensification by combining treatment of the metastatic sites and the primary all together. The contribution of metabolic imaging to better define the target volumes and specify the oligometastatic character allows a better selection of patients. This article aims to define indications of radiotherapy and perspectives of this therapeutic option for de-novo metastatic prostate cancer.

Clinical validation of a prognostic tool in a population of outpatients treated for incurable cancer undergoing anticancer therapy: PRONOPALL study.

BACKGROUND: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase. PATIENTS AND METHODS: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival. RESULTS: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001). CONCLUSION: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice.

First human treatment of resistant neoplastic meningitis by intrathecal administration of MTX plus (125)IUdR.

PURPOSE: Neoplastic meningitis is often the final outcome of disseminated cancer and is rapidly lethal. Its limited treatment relies on systemic or intrathecal chemotherapy with methotrexate (MTX) or thiotepa. When 5-iodo-2'-deoxyuridine labeled with (125)I ((125)IUdR) is incorporated into the DNA of mitotic tumor cells, the Auger electrons emitted during iodine decay are highly cytotoxic. The radiotherapeutic efficacy of (125)IUdR administered intrathecally has also been established in animals bearing spinal cord tumors, and MTX is known to potentiate the response. This approach has not been tested in the clinic. METHODS: A 44-year-old woman, with locally advanced pancreatic cancer, was treated for three years with complete systemic remission, but then relapsed with cytologically proven neoplastic meningitis. The patient was given four successive intrathecal injections of MTX (10 mg) every 12 h and, with the fourth dose, 1850 MBq (125)IUdR, followed by four additional MTX doses. The response was monitored by cytology and CA19.9 (carbohydrate antigen 19.9) levels in the cerebrospinal fluid (CSF) as well as by clinical status of the patient. RESULTS: The follow-up of cytology and CA19.9 levels in the CSF showed dramatic improvement within 26 days followed by a biological relapse on Day +36. There was no evidence of local central nervous system toxicity. Three months later, neoplastic meningitis recurred and meningeal tumor infiltration was observed on magnetic resonance imaging. Six months after MTX-(125)IUdR treatment, the patient died. CONCLUSION: (125)IUdR treatment proved to be feasible without acute neurological toxicity and seemed to have produced a biological response. This attempt provides the basis for designing prospective clinical trials.

[Quantification of prostate movements during radiotherapy]. / Quantification des mouvements prostatiques lors de l'irradiation prostatique.

Decrease treatment uncertainties is one of the most important challenge in radiation oncology. Numerous techniques are available to quantify prostate motion and visualise prostate location day after day before each irradiation: CT-scan, cone-beam-CT-Scan, ultrason, prostatic markers... The knowledge of prostate motion is necessary to define the minimal margin around the target volume needed to avoid mispositioning during treatment session. Different kind of prostate movement have been studied and are reported in the present work: namely, those having a large amplitude extending through out the whole treatment period on one hand; and those with a shorter amplitude happening during treatment session one the other hand. The long lasting movement are mostly anterior-posterior (3 mm standard deviation), secondary in cranial-caudal (1-2 mm standard deviation) and lateral directions (0.5-1 mm standard deviation). They are mostly due to the rectal state of filling and mildly due to bladder filling or inferior limbs position. On the other hand, the shorter movement that occurs during the treatment session is mostly variation of position around a steady point represented by the apex. Ones again, the rectal filling state is the principle cause. This way, during the 20 minutes of a treatment session, including the positioning of the patient, a movement of less than 3 mm could be expected when the rectum is empty. Ideally, real time imaging tools should allow an accurate localisation of the prostate and the adaptation of the dosimetry before each treatment session in a time envelope not exceeding 20 minutes.

[Retrospective analysis of 108 ductal carcinomas in situ of the breast treated by radiosurgery association]. / Analyse rétrospective de 108 carcinomes canalaires in situ mammaires traités par association radiochirurgicale.

PURPOSE: To evaluate survival and prognostic factors of 108 patients with clinically or mammographically detected ductal carcinoma in situ (DCIS), treated from 1980 to 1996 by complete local excision followed by external irradiation. PATIENTS AND METHODS: The median age was 51 (range 37-80). All the patients underwent surgery consisting of a wide resection of the mammary gland harbouring the tumour. The surgical specimens were sent to the pathologists to get information on histology and margin clearance; all the slides were reviewed by one of us to assess the tumoral diameter. External beam therapy was delivered within 8 weeks after surgery. The prescribed irradiation dose was 50 Gy in 25 fractions to be given in 5 weeks. The median duration of follow-up was 93 months (range 40-173). RESULTS: There were nine patients with local recurrence (8.3%); three patients had local recurrence of DCIS and six patients developed invasive breast cancer. The treatment of local recurrence consisted of mastectomy with or without axillary dissection (eight cases) and quadrantectomy (one case). The 5-year and 10-year ipsilateral recurrence-free rate was respectively 92 and 89%. The 10-year cause specific survival was 100%. In univariate analysis, size>or=10 mm, age<45 years old and margin status were significant P=0,02, P=0,03, P=0,005; margin status was significant in multivariate analysis (P<0,02). CONCLUSION: These results are in keeping with those of the literature. They could be improved by the mass screening campaign, which is going on since January 1990 among women aged 50-74 years.

Patient set-up using portal images: 2D/2D image registration using mutual information.

OBJECTIVE: Conformal radiation therapy requires accurate patient set-up for each fraction delivery. Electronic portal imaging devices allow the acquisition of portal images just before and even during dose delivery. However, the quantitative interpretation of these images in determining and correcting the patient's position remains uncertain, and automated methods are therefore being developed. Such methods must be usable for the different radiation therapy techniques. They must be robust and as automated as possible for use in clinical routines. This work was undertaken to establish the feasibility of 2D/2D registration for portal/portal and portal/simulator images in radiotherapy. MATERIALS AND METHODS: This paper describes an automated method based on the combination of calibration algorithms and pixel-based registration algorithms. We present experiments with the different imaging techniques, some of which use a phantom with and without a gold standard. Preliminary results obtained using patient data are also presented and discussed. RESULTS: The results obtained with a phantom demonstrated that this automated method for 2D/2D registration is fast, accurate, and robust, even in the case of blurred images for small treatment fields. CONCLUSIONS: Mutual information is a feasible method for 2D/2D portal/portal and portal/simulator image registration in radiotherapy.

Fast growing cervical carcinomas. A retrospective analysis of 20 IB-IIB FIGO.

INTRODUCTION: Fast growing cervix carcinomas have a pejorative outcome: they may occur quickly after cervical smears qualified as normal - within an interval from 12 to 18 months in women less than 50 years old, and involveing the endocervix. This retrospective analysis is aimed at assessing 5-year outcomes. MATERIALS AND METHODS: Twenty cases of fast-growing cancer of the uterine cervix classified according to the FIGO clinical staging system as IB (n=14), IIA (3), and IIB (3), have been reviewed and compared to a cohort of 160 cases not having this feature. As regard to fast-growing carcinoma, the median age was 41 years (range 25-50), and the median follow-up 22 months (8-213) as compared to 54 years (27-79) and 80 months (5-199) for the reference cohort. The comparison of the two cohorts shows only a difference of breakdown which concerns the histological pelvic lymph nodes status (P<0.05), more often positive in fast-growing forms. The treatment policy was equally distributed between a radio-surgical approach, cesium 137 intracavitary irradiation followed by radical hysterectomy and lymphadenectomy, or a definitive irradiation with pelvic external irradiation followed by cesium 137 intracavitary irradiation. RESULTS: Thirteen deaths are reported in the fast-growing series instead of 54 in the other series. The 5-year overall survival is, respectively, 34 (13-55) vs. 74% (68-82) (P<0.001), the loco-regional-free survival 58 (33-84) vs. 85% (79-81) (P<0.001), the 5-year metastasis-free survival 61 (38-84) vs. 84% (78-90) (P=0. 004). CONCLUSION: These poor results emphasize the need to intensify loco-regional therapy with a concurrent cisplatin-based chemotherapy within the framework of a multidisciplinary approach.

[Image fusion methods for the repositioning of the patient in radiotherapy]. / Méthodes de recalage d'images pour le repositionnement de patients en radiothérapie.

Conformal radiotherapy requires the accurate and reproducible setup of the patient for each fraction delivery. Megavoltage imaging could enable this. This requires the development of image processing and data fusion algorithms. We describe an automated method based on the use of mutual information for registration. Such a method does not require any preliminary segmentation of the images. This method has been extensively tested on phantom as well as on some patient data. The obtained results demonstrated that this automated method for 2D/2D registration is rapid, accurate and robust even in the case of blurred images for small treatment fields.

[Evaluation of a series of 137 carcinomas of the endometrium of stage I TNM/UICC]. / Evaluation d'une série de 137 carcinomes de l'endomètre de stade I TNM/UICC.

PURPOSE: To assess retrospectively the long-term results of the combination of surgery and radiotherapy in carcinoma classified cT1. PATIENTS AND METHODS: From 1974 to 1993, 137 women suffering from endometrial carcinoma cT1Nx-0 M0 were entered into the study. The median age was 62 years (range: 39-85 years) and the median follow up was 67 months (range: 0-224 months). RESULTS: Surgery was performal in 132 women (96.35%). For cT1, the 5-year overall and specific survivals were 81.1% and 84.5%, respectively. The 10-year overall and specific survivals were 68.8% and 82.2%, respectively. Concerning cT1pT1, the 5-year overall and specific survivals, were 83.9% and 87.4%. The 10-year overall and specific survivals were 71.1% and 85%, respectively. Histological grade, pelvic lymph node involvement and myometrial infiltration influence significantly the overall and specific survivals of cT1pT1 tumors. According to multivariate analysis, pelvic lymph node involvement was a powerful prognostic factor for both the overall and specific survivals. If we rule out pelvic lymph node involvement, WHO histological grade was a significant prognostic factor. CONCLUSION: Combination of surgery and radiotherapy is still a common procedure for cT1 tumors. When surgery is done before radiotherapy, tailored irradiation may further take place, according to WHO histological grade and pelvic lymph node status.

Pathological prognostic factors in a series of 137 stage I TNM/UICC endometrial carcinomas.

PURPOSE: We report on the long-term results of combination surgery-radiotherapy in cT1 carcinoma of the endometrium according to prognostic factors. PATIENTS AND METHODS: From 1974 to 1993, 130 women suffering from cT1Nx-O Mo endometrial carcinoma, underwent surgical resection. The median age was 62 years. Thirteen received pre-operative irradiation, two pre-operative brachytherapy followed by post-operative external irradiation and 115 patients (88.35%) underwent post-operative irradiation therapy by brachytherapy or external beam irradiation. RESULTS: The median follow-up is 67 months. Overall and specific survival rates for patients with cT1pT1 tumours were 71.1 and 85% at 10 years. For overall survival, lymph node invasion was the most powerful prognostic factor in the multivariate analysis (P = 0.02). If lymph node invasion is not taken into account, the WHO histological grade exerts a significant prognostic impact (P = 0.001). CONCLUSION: For stage cT1 endometrial carcinoma, primary surgery allows radiotherapy to be adjusted according to the WHO histological grade, myometrial invasion and the pelvic lymph node status.

[Current studies of combined radiotherapy-hormone therapy in localized and locally advanced prostatic cancers]. / Données actuelles de l'association radiothérapie-hormonothérapie dans les cancers de la prostate localisés et localement évolués.

In locally advanced prostate cancer three clinical randomized trials have shown that external irradiation combined with LHRH analogue with or without antiandrogen improved survival: disease-free survival, local recurrence-free survival, metastasis-free survival (P < 0.001). EORTC trial 22863 alone has shown a significant improvement of overall survival (P = 0.001), with an LHRH analogue (goserilin acetate, zoladex) started the first day of irradiation and followed every 4 weeks for 3 years; for RTOG trial 85-31 the same LHRH analogue started during the last week of irradiation and given until relapse increases survival of patients with poor differentiated tumours with gleason score ranging from 8 to 10 (P = 0.03). In locally confined prostate carcinoma randomized trials are ongoing to assess the impact of conventional irradiation or three dimensional conformal radiotherapy with or without adjuvant hormonotherapy.

[Fast growing IB-IIB cancer of the uterine cervix. Apropos of 20 cases]. / Cancers du col utérin IB-IIB à croissance rapide. A propos de 20 cas.

Twenty cases of fast growing cancer of the uterine cervix (14 IB, three IIA, three IIB FIGO), the definition of which is specified, have been reviewed and compared to a cohort of 160 cases not having this feature, to assess their outcomes. In regard to fast growing carcinomas, the median age was 41 (25-50) years and the median follow-up 22 months (8-213) as compared to 54 years (27-79) and 80 months (5-199) for the reference cohort. The comparison of the two cohorts shows only a difference of breakdown which concerns the pelvic lymph nodes status (P < 0.05, chi 2). Thirteen deaths are reported in the fast growing series instead of 54 in the other series. The 5-year overall survival is respectively 34% (13-55) versus 74% (68-82), the loco-regional free survival 58% (33-84) versus 85% (79-81) (P < 0.001), the 5-year metastasis free survival 61% (38-84) versus 84% (78-90) (P = 0.004). This particular form needs a multidisciplinary approach, and the local regional treatment has to be intensified.