Luca Cionini

Primary Tumor Response to Preoperative Chemoradiation With or Without Oxaliplatin in Locally Advanced Rectal Cancer: Pathologic Results of the STAR-01 Randomized Phase III Trial

PURPOSE To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. PATIENTS AND METHODS Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m(2)/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m(2) weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here. RESULTS Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014). CONCLUSION Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.

Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients.

PURPOSE In the literature, a favorable prognosis was observed for complete pathologic response after preoperative therapy (ypCR) in patients with locally advanced rectal cancer. The aim of this study is to verify whether ypCR predicts a favorable outcome in a large series of patients. METHODS AND MATERIALS The Gastro-Intestinal Working Group of the Italian Association of Radiation Oncology collected clinical data for 566 patients with ypCR (ypT0N0) after neoadjuvant therapy. Eligibility criteria included locally advanced rectal cancer with no evidence of metastases at the time of diagnosis, evidence of ypCR after preoperative radiotherapy +/- chemotherapy (CT). RESULTS Median radiation dose was 50 Gy. A total of 527 patients (93%) received one of 12 different neoadjuvant CT schedules. Sphincter preservation, anteroposterior resection, and endoscopic surgery were performed in 73%, 22%, and 5% of patients, respectively. Adjuvant CT was administered to 22% of patients. Median follow-up was 46.4 months. Locoregional recurrence occurred in 7 patients (1.6%). Distant metastases occurred in 49 patients (8.9%). Overall, 5-year rates of disease-free survival, overall survival, and cancer-specific survival were 85%, 90%, and 94%, respectively. In multivariate analysis, only age and clinical stage statistically correlated with survival outcome. Adjuvant CT was still of borderline significance (worse for adjuvant CT). No relation was found between survival and neoadjuvant CT schedules. CONCLUSION A ypCR after neoadjuvant therapy identified a favorable group of patients, even in this large series of 566 patients collected in 61 centers. Locoregional recurrence occurred only in 1.6% patients.

Nomograms for Predicting Local Recurrence, Distant Metastases, and Overall Survival for Patients With Locally Advanced Rectal Cancer on the Basis of European Randomized Clinical Trials

PURPOSE The purpose of this study was to develop accurate models and nomograms to predict local recurrence, distant metastases, and survival for patients with locally advanced rectal cancer treated with long-course chemoradiotherapy (CRT) followed by surgery and to allow for a selection of patients who may benefit most from postoperative adjuvant chemotherapy and close follow-up. PATIENTS AND METHODS All data (N = 2,795) from five major European clinical trials for rectal cancer were pooled and used to perform an extensive survival analysis and to develop multivariate nomograms based on Cox regression. Data from one trial was used as an external validation set. The variables used in the analysis were sex, age, clinical tumor stage stage, tumor location, radiotherapy dose, concurrent and adjuvant chemotherapy, surgery procedure, and pTNM stage. Model performance was evaluated by the concordance index (c-index). Risk group stratification was proposed for the nomograms. RESULTS The nomograms are able to predict events with a c-index for external validation of local recurrence (LR; 0.68), distant metastases (DM; 0.73), and overall survival (OS; 0.70). Pathologic staging is essential for accurate prediction of long-term outcome. Both preoperative CRT and adjuvant chemotherapy have an added value when predicting LR, DM, and OS rates. The stratification in risk groups allows significant distinction between Kaplan-Meier curves for outcome. CONCLUSION The easy-to-use nomograms can predict LR, DM, and OS over a 5-year period after surgery. They may be used as decision support tools in future trials by using the three defined risk groups to select patients for postoperative chemotherapy and close follow-up (http://www.predictcancer.org).

Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: Pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial

CRA4008 Background: Oxaliplatin (OXA) enhances the efficacy of FU-based chemotherapy in colon cancer. This randomized phase III trial investigated the effect of adding OXA to preoperative (preop) FU-based pelvic chemoradiation (CRT) in patients (pts) with locally-advanced rectal cancer. METHODS Eligibility required a resectable, biopsy-proven rectal adenocarcinoma within 12 cm from the anal verge with radiological evidence of perirectal fat or lymphnode involvement. Randomization was between infused FU (225 mg/msq/day) concomitant to external-beam pelvic radiation (50.4 Gy in 28 daily fractions) (arm A) or the same regimen + weekly OXA (60 mg/msq × 6) (Arm B). Surgery was scheduled 6-8 weeks after completing CRT. Overall survival was the primary endpoint. A protocol-planned analysis of local tumor response to preop treatment (secondary end-point) is the object of this report. RESULTS 747 pts from 41 Italian centers were randomized between 12/2003 and 8/2008 (arm A/B: 379/368). Pretreatment characteristics in arm A/B: median age 63/62 years; male:female 2:1; median distance from anal verge 6 cm; T4 16/14%, N+ 63/65%. Overall grade 3-4 toxicity rates on treated pts (mainly diarrhoea) were 8% and 24% (arm A/B, p<0.001). 96/90% of pts (arm A/B) received > 90% of the planned RT. 82% of Arm B pts had > 5 oxa courses. 358/342 pts (arm A/B) had surgery at a median of 52/53 days from the end of CRT, 14 pts in each arm were not operated (progression 8, death 5, other/unknown 15) and surgery data are not yet available for 19 pts. Pathologic response data analyzed on the randomized population are reported in the table . CONCLUSIONS The addition of weekly OXA to standard FU-based preop CRT significantly increases toxicity without affecting local tumor response. The reduced pathologic M+ rate suggests a potential effect on distant micrometastases. Longer follow-up is needed to assess the impact on efficacy endpoints. [Table: see text] No significant financial relationships to disclose.

Results of a european randomized trial of Etanidazole combined with radiotherapy in head and neck carcinomas

Purpose: The aim of the study was to evaluate the efficacy and toxicity of Etanidazole, a hypoxic cell sensitizer, combined with radiotherapy in the treatment of head and neck squamous cell carcinoma. Methods and Materials: A total of 374 patients from 27 European centers were included in this trial between 1987 and 1990. Treatment was either conventional radiotherapy alone (between 66 Gy in 33 fractions and 74 Gy in 37 fractions, 5 fractions per week), or the same radiotherapy dose plus Etanidazole 2 g/m 2 , three times weekly for 17 doses. A minimization procedure, balancing for center, site, and T stage (T1-T3 vs. T4) was used for randomization. Results: Among the 187 patients in the Etanidazole group, 82% received at least 14 doses of the drug. Compliance to the radiotherapy protocol was 92% in the Etanidazole group and 88% in the control group; the main cause of deviation was acute toxicity, which was observed at an equal rate in the two treatment groups. Fifty-two cases of Grade 1 to 3 peripheral neuropathy were observed in the Etanidazole group vs. 5 cases, all of Grade 1, in the control group (p < 0.001). The 2-year actuarial loco-regional control rates were 53% in the Etanidazole group and 53% in the control group (p = 0.93), and the overall 2-year survival rates were 54% in each group (p = 0.99). Conclusion: Adding Etanidazole to conventional radiotherapy did not afford any benefit for patients with head and neck carcinoma. This study failed to confirm the hypothesis of a benefit for patients with N0-N1 disease, which had been suggested by the results of a previous study (10).

Combined Nd-YAG laser/HDR brachytherapy versus Nd-YAG laser only in malignant central airway involvement: a prospective randomized study

BACKGROUND Laser debulking and prosthetic stents are useful modalities in the palliative treatment of initial inoperable or recurrent lung cancer. Recently, endobrochial brachytherapy was introduced to extend the duration of palliation and reduce the number of endoscopic treatments. This trial compares Nd-YAG laser alone and associated to high dose rated (HDR)-brachytherapy. PATIENTS AND METHODS From 1995 to 1998, 29 consecutive patients, with non-small cell lung cancer (NSCLC) and central airway involvement, were randomized in two groups: group 1 (15 patients) received Nd-YAG laser only; group 2 (14 patients) underwent a combined Nd-YAG laser/ HDR brachytherapy treatment. RESULTS There was no mortality or morbidity related to the treatment. The period free from symptoms was 2.8 months for group 1 and increased to 8.5 months in group 2 (P<0.05). The diseases progression free period grew from 2.2 months of group 1 to 7.5 months of group 2 (P<0.05) and the number of further endoscopic treatment reduced from 15 to 3 (P<0.05). CONCLUSION The results confirm the potential of brachytherapy to prolong relief from symptoms, lessen disease progression and reduce costs of treatment. A detailed analysis is presented of both groups.

Profile of radiotherapy departments contributing to the Cooperative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer.

PURPOSE Since 1982, the Radiotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC) is carrying out a Quality Assurance program that includes the evaluation of the structure and human resources of 50 centers actively participating in protocols of clinical research in radiotherapy. METHODS AND MATERIALS One or two site visits were made by a team of radiation physicists and physicians. A detailed questionnaire was circulated to these radiotherapy centers to collect and update standardized figures on the status and activities of each center, to clarify some obscurities encountered during on-site visits, and to extend investigations to issues that were not addressed during local audits. RESULTS This article reports on departmental infrastructure, staff and equipment workload, and quality control procedures carried out by single institutions. Large variations in equipment and staff are observed among participating centers. Comparisons between data collected in the early 1980s and during a recent update show no difference in workload per megavoltage equipment and per simulator. The number of cancer patients treated per year per radiotherapist seems to slightly diminish, especially in centers that experienced a considerable staff shortage a few years ago. The most significant improvement is observed for the number of cases treated per year per member of the radiation physics team. The radiographers workload shows an opposite trend. CONCLUSIONS Our database provides participating centers with strong comparative arguments to correct staff and equipment unbalances and to convince administrative authorities of priorities in decision making. The current analysis shows that the situation for equipment is unchanged in comparison with that observed 6 years ago. Efforts have to be put forth in some institutions to reduce the workload at simulators. A tentative profile and guidelines for minimum recommendations for European radiotherapy departments involved in clinical research are presented.

Perioperative High-Dose-Rate Brachytherapy in the Treatment of Recurrent Malignant Gliomas

Purpose:To assess the feasibility and effectiveness of perioperative high-dose-rate brachytherapy for recurrent malignant gliomas.Patients and Methods:Between 2005 and 2008, 21 patients (14 males and seven females) with relapsed malignant glioma underwent a second surgery followed by a brachytherapy implant in the surgical cavity. Median age was 60 years, and median Karnofsky performance status 80. A single fraction of 18 Gy specified at 5 mm depth was administered perioperatively. Then, the applicator was removed nonsurgically. Mean postoperative hospitalization time was 3 days.Results:At the time of analysis, 15 patients (71%) had died and six (29%) were alive. Median follow-up was 32.3 months. Median overall survival from diagnosis amounted to 21.7 months. Median survival after recurrence was 8.0 months, and 6-month progression-free survival 42%. Patients were stratified into classes according to the prognostic recursive partitioning analysis.Conclusion:Perioperative brachytherapy has proven to be safe and well tolerated in patients with recurrent malignant glioma. No severe toxicity was reported, and the treatment has proven to be effective in symptomatic recurrences of malignant gliomas.Hintergrund und Ziel:Beurteilung der Durchführbarkeit und Wirksamkeit einer perioperativen High-Dose-Rate-(HDR-)Brachytherapie bei rezidivierenden malignen Gliomen.Patienten und Methodik:Zwischen 2005 und 2008 wurden 21 Patienten (14 Männer und sieben Frauen) mit rezidivierenden malignen Gliomen einer zweiten Operation zugeführt, gefolgt von einer HDR-Brachytherapie des Rezidivtumorbetts. Das durchschnittliche Alter der Patienten betrug 60 Jahre, der durchschnittliche Karnofsky-Performance-Status 80. Perioperativ wurde eine Einzeldosis von 18 Gy appliziert, dosiert auf 5 mm Gewebetiefe. Anschließend wurde der Applikator entfernt. Die mittlere Dauer des postoperativen Krankenhausaufenthalts lag bei 3 Tagen.Ergebnisse:Zum Zeitpunkt der Analyse waren 15 Patienten (71%) gestorben. Die mediane Nachbeobachtungszeit betrug 32,3 Monate. Die mediane Gesamtüberlebenszeit lag bei 21,7 Monaten. Das mediane Überleben nach Rezidivdiagnose betrug 8,0 Monate, das progressionsfreie 6-Monats-Überleben 42%. Die Patienten wurden gemäß der prognostischen RPA („recursive partitioning analysis“) in Klassen eingeteilt.Schlussfolgerung:Diese Untersuchung hat gezeigt, dass die perioperative HDR-Brachytherapie bei Patienten mit rezidivierten malignen Gliomen sicher und gut verträglich ist. Es wurde keine schwere Toxizität beobachtet. Die Ergebnisse bestätigen die Gültigkeit und Wirksamkeit einer solchen Behandlung bei symptomatischem Auftreten eines malignen Glioms.

Postoperative pelvic radiotherapy with or without elective irradiation of para-aortic nodes and liver in rectal cancer patients. A controlled clinical trial of the EORTC Radiotherapy Group.

OBJECTIVE The purpose of this randomized multicenter study was to assess the impact on disease free and overall survival of low dose irradiation to para-aortic nodes and liver in patients with a locally advanced resected rectal cancer receiving a 50 Gy postoperative pelvic radiotherapy. PATIENTS AND METHODS Main inclusion criteria were: a curative resection for a histologically proved carcinoma of the rectum, Gunderson-Sosin stages B2-B3, C1-C3, age <70 years. The patients were randomized between pelvic irradiation (Lim-XRT): 50 Gy in 25 fractions over 5 weeks and extended irradiation (Ext-XRT): same scheme/doses in the pelvis and extended fields on para-aortic nodes and liver, delivering 25 Gy in 19 fractions over 25 days. From 1983 to 1992, 484 patients were enrolled by 18 EORTC institutions and 29 patients were ineligible. The end-points were local and distant relapses, toxicity and survival. RESULTS Compliance to treatment: 87.2% in Lim-XRT arm and 71.8% in Ext-XRT arm. Moderate acute hematological and hepatic toxicities were significantly increased in Ext-XRT arm. Among 325 patients at risk, 44 suffered a severe intestinal complication requiring surgery in 29. The 5- and 10-year estimates of disease free survival were respectively 42 and 31% in Lim-XRT arm and 47 and 31% in Ext-XRT arm (ns). The corresponding figures for overall survival were respectively 45 and 40% in Lim-XRT arm and 48 and 37% in Ext-arm (ns). The 10 years estimate of intra-pelvic failures was approximately 30% in both arms. Patients in Ext-arm appeared to have a slight shorter interval free of liver metastases (P=0.047). CONCLUSION Low dose irradiation to the para-aortic nodes and liver did not improve survival for patients with resected adenocarcinoma of the rectum.

Accuracy of endoanal ultrasound in the follow-up assessment for squamous cell carcinoma of the anal canal treated with radiochemotherapy

BackgroundRadiochemotherapy has largely replaced surgery in the treatment for squamous cell cancer of the anal canal. Transanal ultrasonography is well documented as an important investigation method in the management of anal carcinoma. This study aimed to evaluate the accuracy of endoanal ultrasound in the study of the postradiation findings and to distinguish between postradiation fibrosis, residual tumor, and local recurrence.MethodsThe study enrolled 16 consecutive patients with biopsy-proven squamous carcinoma of the anal canal between 2003 and 2006. All the patients underwent a pretreatment and at least four posttreatment endosonographies, according to the follow-up period. All the patients were treated with the same radiochemotherapy protocol.ResultsNine patients had stage uT2 disease; none had uT3 disease; and seven had uT4 disease. There was no evidence of residual tumor in the T2 group after treatment. In the T4 patients after treatment, ultrasound demonstrated tumor regression or abnormalities considered to be radiation-induced changes rather than residual diseases. Only for three patients was a posttreatment biopsy performed to evaluate recurrence (two uT2 and one uT4). Surgical treatment of recurrence was performed for two uT4 patients.ConclusionsEndoanal ultrasound is a safe and effective method for evaluating and following anal cancer before and after treatment. Experience and evaluation during the period of the ultrasonographic abnormalities could give a clear idea concerning the evolution of the anal tumors treated with radiochemotherapy.