Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study.

BACKGROUND: EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy-irrespective of timing-significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results. METHODS: We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m(2) per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m(2) per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523. FINDINGS: 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8-13·1), 10-year overall survival was 49·4% (95% CI 44·6-54·1) for the preoperative radiotherapy group and 50·7% (45·9-55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83-1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0-56·4) for the adjuvant chemotherapy group and 48·4% (43·6-53·0) for the surveillance group (HR 0·91, 95% CI 0·77-1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5-48·8) for the preoperative radiotherapy group and 46·4% (41·7-50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79-1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2-51·6) for the adjuvant chemotherapy group and 43·7% (39·1-48·2) for the surveillance group (HR 0·91, 95% CI 0·77-1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1-27·6) with radiotherapy alone, 11·8% (7·8-15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1-18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7-15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22). INTERPRETATION: Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required. FUNDING: EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs.

Phase II study of preoperative radiation plus concurrent daily tegafur-uracil (UFT) with leucovorin for locally advanced rectal cancer.

BACKGROUND: Considerable variation in intravenous 5-fluorouracil (5-FU) metabolism can occur due to the wide range of dihydropyrimidine dehydrogenase (DPD) enzyme activity, which can affect both tolerability and efficacy. The oral fluoropyrimidine tegafur-uracil (UFT) is an effective, well-tolerated and convenient alternative to intravenous 5-FU. We undertook this study in patients with locally advanced rectal cancer to evaluate the efficacy and tolerability of UFT with leucovorin (LV) and preoperative radiotherapy and to evaluate the utility and limitations of multicenter staging using pre- and post-chemoradiotherapy ultrasound. We also performed a validated pretherapy assessment of DPD activity and assessed its potential influence on the tolerability of UFT treatment. METHODS: This phase II study assessed preoperative UFT with LV and radiotherapy in 85 patients with locally advanced T3 rectal cancer. Patients with potentially resectable tumors received UFT (300 mg/m/2/day), LV (75 mg/day), and pelvic radiotherapy (1.8 Gy/day, 45 Gy total) 5 days/week for 5 weeks then surgery 4-6 weeks later. The primary endpoints included tumor downstaging and the pathologic complete response (pCR) rate. RESULTS: Most adverse events were mild to moderate in nature. Preoperative grade 3/4 adverse events included diarrhea (n = 18, 21%) and nausea/vomiting (n = 5, 6%). Two patients heterozygous for dihydropyrimidine dehydrogenase gene (DPYD) experienced early grade 4 neutropenia (variant IVS14+1G > A) and diarrhea (variant 2846A > T). Pretreatment ultrasound TNM staging was compared with postchemoradiotherapy pathology TN staging and a significant shift towards earlier TNM stages was observed (p < 0.001). The overall downstaging rate was 42% for primary tumors and 44% for lymph nodes. The pCR rate was 8%. The sensitivity and specificity of ultrasound for staging was poor. Anal sphincter function was preserved in 55 patients (65%). Overall and recurrence-free survival at 3 years was 86.1% and 66.7%, respectively. Adjuvant chemotherapy was administered to 36 node-positive patients (mean duration 118 days). CONCLUSION: Preoperative chemoradiotherapy using UFT with LV plus radiotherapy was well tolerated and effective and represents a convenient alternative to 5-FU-based chemoradiotherapy for the treatment of resectable rectal cancer. Pretreatment detection of DPD deficiency should be performed to avoid severe adverse events.

High-Dose Hypofractionated Radiation Therapy for Noncompressive Vertebral Metastases in Combination With Zoledronate: A Phase 1 Study.

INTRODUCTION: Hypofractionated stereotactic radiation therapy (HSRT) for vertebral metastases gives good results in terms of local control but increases the risk of fracture in the treated volume. Preclinical and clinical studies have shown that zoledronate not only reduces the risk of fracture and stimulates osteoclastic remodeling but also increases the immune response and radiosensitivity. This study aimed to evaluate the tolerability and effectiveness of zoledronate in association with radiation therapy. PATIENTS AND METHODS: We conducted a multicenter phase 1 study that combined HSRT (3 × 9 Gy) and zoledronate in patients with vertebral metastasis (NCT01219790). The principal objective was the absence of spinal cord adverse reactions at 1 year. The secondary objectives were acute tolerability, the presentation of a bone event, local tumor control, pain control, progression-free survival, and overall survival. RESULTS: Thirty patients (25 male, 5 female), median age 66 years, who were followed up for a median period of 19.2 months, received treatment for 49 vertebral metastases. A grade 3 acute mucosal adverse event occurred in 1 patient during the treatment and in 2 more at 1 month. No late neurologic adverse events were reported at 1 year. The mean pain scores diminished significantly at 1 month (1.35; P=.0125) and 3 months (0.77; P<.0001) compared with pain scores at study entry (2.49). Vertebral collapse in the irradiated zone occurred in 1 (2%) treated vertebra. Control of local disease was achieved in 94% of irradiated patients (3 local recurrences). CONCLUSION: The combination of zoledronate and HSRT in the treatment of vertebral metastasis is well tolerated and seems to reduce the rate of vertebral collapse, effectively relieve pain, and achieve good local tumor control with no late neurologic adverse effects.

Hypofractionated irradiation in elderly patients with breast cancer after breast conserving surgery and mastectomy : Analysis of 205 cases.

BACKGROUND: Several randomized trials and meta-analyses confirmed a wide benefit of radiotherapy (RT), both after breast conserving surgery (BCS) and mastectomy. However, many elderly women don't receive RT. Hypofractionated (HF) RT allows « simplified ¼ and more accessible treatments with equivalent results to classic RT in three large randomized trials. However, there are few available data on HF-RT for nodal irradiation, as well as for the boost. METHODS: We evaluated patients treated for IBC by HF-RT between 2004 and 2012 in two regional cancer centres. We used an original scheme delivering 45 Gy in 15 fractions three times a week, both after BCS or mastectomy, with or without nodal irradiation. After BCS, a 9 Gy boost in 3 fractions was delivered. Local, regional and distant recurrences were assessed, as well as acute and late cutaneous, cardiac or pulmonary toxicities. RESULTS: 205 patients were analysed, 116 after BCS (57 %) and 89 after mastectomy (43 %). Median age was 81 years (range: 52-91); 44 % had axillary nodal involvement (pN+). The Nottingham Prognostic Index (NPI) scored 0, 1, 2 and 3 in 10 %, 27 %, 44 % and 19 % of the cases. A nodal HF-RT was delivered in 65 patients (32 %) and boost in 98 patients (84 % of BCS) by 9 Gy/3 fr scheme. Fifty (24 %) patients underwent chemotherapy and 156 (75 %) hormonal treatment. With a 49-month median follow-up, 3/116 (2.6 %) patients and 4/89 (4.5 %) had local recurrence (LR) after BCS and mastectomy, respectively. The overall 5-year LR rate was 4.4 %. In univariate and multivariate analysis, LR risk factors were: high NPI (HR 5.46; p = 0.028), and triple negative tumour (HR 9.78; p = 0.006). Only 8 (4.5 %) patients had grade III skin toxicity; 29 (14 %) late fibrosis and 16 (8 %) telangiectasia. No pulmonary or cardiac toxicity was observed. CONCLUSION: Our HF-RT scheme (with or without nodal irradiation) confirms in elderly patients the data from randomized trials, both after BCS or mastectomy. Toxicity seems very acceptable but requires a longer follow-up. A larger evaluation is still ongoing in several other centres in France.

[Prognostic value of endorectal ultrasonography in rectal cancer: results of a multifactorial analysis]. / Valeur pronostique de l'echo-endoscopie dans le cancer du rectum: résultats d'une analyse multifactorielle.

INTRODUCTION: No study has evaluated the prognostic value of initial endorectal ultrasonography (ERUS) in rectal cancer (RC). AIM: To assess the prognostic value of initial ERUS in operated patients with RC. MATERIAL AND METHODS: Eighty-four patients with non metastatic RC were examined by ERUS before treatment. Forty-two received preoperative radiation therapy and they were resected 7 weeks later on average. The prognostic value of uTN and pTN classification was analysed by means of a Cox model, taking into account the realization of preoperative radiation therapy. RESULTS: In the univariate analysis, 4 variables were predictive of prognosis: elevation of alkaline phosphatases, the degree of circonference, the extension of the resection margin, and the involvement of perirectal lymph nodes. The multivariate analysis showed that when considering only pTN and uTN classifications, only uT and pN kept a significant prognostic value. The better prognostic role of uT was due to a close relationship with preoperative radiation therapy which was responsible for a significant downstaging. CONCLUSION: Since preoperative radiotherapy has become a standard in France, the prognostic value of ERUS has emerged, better than pTN classification when radiotherapy has been preoperatively applied. Other prognostic factors should be investigated in a more homogeneous population of patients, all presurgically irradiated

[Biochemical monitoring of prostate cancer treated exclusively by radiotherapy: prognostic value of pretreatment PSA, PSA nadir and PSA half-life]. / Suivi biologique du cancer de la prostate traité par radiothérapie exclusive: valeur pronostique du PSA pré-thérapeutique, du PSA Nadir et de la demi-vie du PSA.

OBJECTIVES: Retrospective evaluation of the prognostic value of pretreatment PSA, PSA nadir and PSA half-life compared to grade and stage after treatment of prostate cancer by radiotherapy. PATIENTS AND METHODS: 122 patients (19 T1 (15.6%), 31 T2a (25.4%), 26 T2b (21.3%), 20 T3a (16.4%), 19 T3b (15.6%), 7 Tx (5.7%)) treated by exclusive radiotherapy were studied with a median follow-up of 75.4 months. Treatment consisted of high energy irradiation to the prostate for 31 patients (25.4%) and to the pelvis and prostate for 91 patients (74.6%). PSA was assayed retrospectively. The influence of various parameters on the absence of laboratory failure, defined according to the ASTRO criteria, and on overall survival was studied by univariate and multivariate analysis with a Cox model. RESULTS: 29.5% of patients did not develop any biochemical recurrence after a mean follow-up of 82 months, while biochemical recurrence occurred in 70.5% of patients after a mean interval of 5 months. Among these patients, 28 (33%) developed clinical recurrence after a mean interval of 26 months (4 to 80 months) leading to death in 17 cases. The modalities of irradiation and pretreatment PSA had no influence on the prognosis. The median PSA nadir of patients without recurrence was 0.24 ng/ml. The recurrence rate was lower for a PSA nadir less than 0.5 ng/ml for biochemical recurrence (45.5% vs 86.8%) (p < 0.0001) and clinical recurrence (9.1% vs 31.6%) (p < 0.05). On multivariate analysis, the PSA nadir (p = 0.009), PSA half-life (p < 0.001) and Gleason score (p = 0.004) were prognostic factors influencing survival, while PSA nadir was the only prognostic factor for biochemical recurrence (p = 0.001). Classification of patients into two groups with a significantly different prognosis according to the presence or absence of at least two favourable prognostic factors (PSA nadir less than 0.5 ng/ml, Gleason score less than 7, PSA half-life greater than 6 months) showed that the 9-year mortality rate was twofold higher in the poor prognosis group than in the good prognosis group (85.5% versus 38.6%). CONCLUSION: A nadir PSA level less than 0.5 ng/ml, a PSA half-life greater than 6 months and a Gleason score less than 7 were predictive of a low risk of biochemical recurrence and prolonged survival after treatment by exclusive radiotherapy, in our patients.

Radiation plus docetaxel and cisplatin in locally advanced pancreatic carcinoma: a non-comparative randomized phase II trial.

BACKGROUND: We performed a randomized, non-comparative phase II study evaluating docetaxel in combination with either daily continuous (protracted IV) 5-fluorouracil or cisplatin administered weekly, concurrent to radiotherapy in the treatment of locally advanced pancreatic carcinoma. Results of the docetaxel plus cisplatin regimen are reported. METHODS: Forty chemotherapy-naive patients with locally advanced pancreatic carcinoma were randomly assigned to receive 5-fluorouracil and docetaxel or docetaxel 20mg/m(2) and cisplatin 20mg/m(2)/week, plus concurrent radiotherapy for 6 weeks. The radiation dose to the primary tumour was 54Gy in 30 fractions. The trial's primary endpoint was the 6-month crude non-progression rate. RESULTS: 51 patients from 7 centres were included in the docetaxel-cisplatin treatment group. Six-month non-progression rate was 39% (95% confidence interval: 26-53). Median overall survival was 9.6 months (95% confidence interval: 2.4-60.7); 6 complete and 8 partial responses were obtained. Six patients survived more than 2 years after their inclusion in the trial. Grade ≥3 toxicity was reported in 63% of patients; no treatment-related death occurred. Severe toxicities were mainly anorexia (22%), vomiting (20%) and fatigue (24%). CONCLUSIONS: Despite inadequate efficacy according to the main end point, this regimen gave a satisfactory rate of objective response (27%) with tolerable toxicity.