Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN).

CONTEXT: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. OBJECTIVE: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. EVIDENCE ACQUISITION: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. EVIDENCE SYNTHESIS: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. CONCLUSIONS: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. PATIENT SUMMARY: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.

Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis.

BACKGROUND: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups. METHODS: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855. FINDINGS: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group. INTERPRETATION: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended. FUNDING: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.

YpN0 rectal cancer patients with sterilized lymph nodes after neoadjuvant chemoradiotherapy are of greater risk of recurrence.

BACKGROUND: Indication for adjuvant chemotherapy in ypN0 rectal cancer patients after chemoradiotherapy (CRT) is debated. The clinical significance of the presence of sterilized lymph nodes (LNS) in ypN0 patients remains to be determined. AIMS: To assess the prognostic value of LNS in ypN0 rectal cancers after neoadjuvant CRT. METHODS: From 2006-2016, 235 patients underwent TME surgery for non-metastatic mid-low rectal cancer after CRT. A lymph node was considered sterilized if there were signs of treatment response (fibrosis, necrosis or mucus) without residual tumor cells. RESULTS: 180 patients (77%) were classified ypN0 and 55 (23%) ypN+. LNS was present in 20 patients (9%). In ypN0 patients, 5-year OS was similar between patients with and without LNS. In contrast, 5-year DFS was significantly lower in ypN0/LNS + patients (58% vs. 78%, p = 0.043) and was similar to those staged ypN+. In multivariate analysis, two factors were independent predictors of DFS: mesorectal grading (OR = 3.14; 95%CI: 1.10-8.34; p = 0.033) and the presence of LNS (OR = 3.93, 95% CI: 1.06-11.81, p = 0.042) CONCLUSION: The presence of LNS in ypN0 rectal cancer after neoadjuvant CRT is associated with an increased risk of recurrence and may be taken into account for the discussion of adjuvant chemotherapy.

Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas: Results of the GORTEC 2007-02 Phase III Randomized Trial.

PURPOSE: Both concurrent chemoradiotherapy (CT-RT) and cetuximab radiotherapy (cetux-RT) have been established as the standard of care for the treatment of locally advanced squamous cell carcinoma of the head and neck. It was not known whether the addition of induction chemotherapy before cetux-RT could improve outcomes compared with standard of care CT-RT. PATIENTS AND METHODS: The current trial was restricted to patients with nonmetastatic N2b, N2c, or N3 squamous cell carcinoma of the head and neck and fit for taxotere, cisplatin, fluorouracil (TPF). Patients were randomly assigned to receive three cycles of TPF followed by cetux-RT versus concurrent carboplatin fluorouracil and RT as recommended in National Comprehensive Cancer Network guidelines. The trial was powered to detect a hazard ratio (HR) of 0.66 in favor of TPF plus cetux-RT for progression-free survival at 2 years. The inclusion of 180 patients per arm was needed to achieve 80% power at a two-sided significance level of .05. RESULTS: Between 2009 and 2013, 370 patients were included. All patients and tumors characteristics were well balanced between arms. There were more cases of grade 3 and 4 neutropenia in the induction arm, and the induction TPF was associated with 6.6% treatment-related deaths. With a median follow-up of 2.8 years, 2-year progression-free survival was not different between both arms (CT-RT, 0.38 v TPF + cetux-RT, 0.36; HR, 0.93 [95% CI, 0.73 to 1.20]; P = .58). HR was 0.98 (95% CI, 0.74 to 1.3; P = .90) for locoregional control and 1.12 (95% CI, 0.86 to 1.46; P = .39) for overall survival. These effects were observed regardless of p16 status. The rate of distant metastases was lower in the TPF arm (HR, 0.54 [95% CI, 0.30 to 0.99]; P = .05). CONCLUSION: Induction TPF followed by cetux-RT did not improve outcomes compared with CT-RT in a population of patients with advanced cervical lymphadenopathy.

Very accelerated radiotherapy or concurrent chemoradiotherapy for N3 head and neck squamous cell carcinoma: Pooled analysis of two GORTEC randomized trials.

OBJECTIVE: To analyze the outcome of N3 patients treated with very accelerated radiotherapy (VART) or different schedules of concurrent chemoradiotherapy (CRT) within two phase III trials. PATIENTS AND METHODS: Data of 179 patients with N3 HNSCC from two GORTEC randomized trials (96-01 and 99-02) were pooled. Patients received either VART: 64.8Gy/3.5weeks or one of the 3 following CRT regimens: Conventional CRT: 70Gy/7weeks+3 cycles carboplatin-5FU; Moderately accelerated CRT: 70Gy/6weeks+2 cycles carboplatin-5FU; Strongly intensified CRT: 64Gy/5weeks+cisplatin (days 2, 16, 30) and 5 FU (days 1-5, 29-33) followed by 2 cycles adjuvant cisplatin-5FU. RESULTS: Median follow-up was 13.3 and 5.2years for GORTEC 96-01 and GORTEC 99-02, respectively. Five-year overall survival (OS) was 13.8%. No significant difference was observed between CRT versus VART in terms of OS (hazard ratio [HR]: 0.93, p=0.68), loco-regional progression (HR: 0.70, p=0.13), or distant progression (HR: 0.86, p=0.53). OS was worse for patients with T3-4 tumors versus early T stage (11.0% versus 25.7%, p=0.015). In multivariate analysis, the oropharyngeal subsite presented a higher risk of distant metastasis (as first event 46.5% vs 19.2%, p<0.001),). A significant interaction between treatment modalities and subsites has been observed concerning loco-regional and distant failures. CONCLUSION: The outcome of N3 HNSCC was extremely poor despite treatment intensification and no difference between CRT and VART. Both distant metastases and loco-regional failures remain important treatment challenge.

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.

Early choline levels from 3-tesla MR spectroscopy after exclusive radiation therapy in patients with clinically localized prostate cancer are predictive of plasmatic levels of PSA at 1 year.

PURPOSE: To investigate the time course response of prostate metabolism to irradiation using magnetic resonance spectroscopy (MRS) at 3-month intervals and its impact on biochemical control. METHODS AND MATERIALS: Between January 2008 and April 2010, 24 patients with localized prostate cancer were prospectively enrolled in the Evaluation of the Response to Irradiation with MR Spectroscopy (ERIS) trial. All the patients had been treated with intensity-modulated radiation therapy with or without long-term adjuvant hormonal therapy (LTHT) and underwent 3-T MRS and prostate-specific antigen (PSA) assays at baseline and every 3 months thereafter up to 12 months. RESULTS: After radiation, the mean normalized citrate level (citrate/water) decreased significantly over time, both in the peripheral zone (PZ) (p = 0.0034) and in the entire prostate (p = 0.0008), whereas no significant change was observed in mean normalized choline levels (choline/water) in the PZ (p = 0.84) and in the entire prostate (p = 0.95). At 6 months after radiation, the mean choline level was significantly lower in the PZ for patients with a PSA value of ≤0.5 ng/mL at 12 months (4.9 ± 1.7 vs. 7.1 ± 1.5, p = 0.0378). Similar results were observed at 12 months in the PZ (6.2 ± 2.3 vs. 11.4 ± 4.1, p = 0.0117 for choline level and 3.4 ± 0.7 vs. 16.1 ± 6.1, p = 0.0054 for citrate level) and also in the entire prostate (6.2 ± 1.9 vs. 10.4 ± 3.2, p = 0.014 for choline level and 3.0 ± 0.8 vs. 13.3 ± 4.7, p = 0.0054 for citrate level). For patients receiving LTHT, there was no correlation between choline or citrate levels and PSA value, either at baseline or at follow-up. CONCLUSIONS: Low normalized choline in the PZ, 6 months after radiation, predicts which patients attained a PSA ≤0.5 ng/mL at 1 year. Further analyses with longer follow-up times are warranted to determine whether or not these new biomarkers can conclusively predict the early radiation response and the clinical outcome for patients with or without LTHT.

Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group.

PURPOSE: European Organisation for Research and Treatment of Cancer (EORTC) trial 22921 compared adjuvant fluorouracil-based chemotherapy (CT) to no adjuvant treatment in a 2 x 2 factorial trial with randomization for preoperative (chemo)radiotherapy in patients with resectable T3-4 rectal cancer. The results showed no significant impact of adjuvant CT on progression-free or overall survival, although a difference seemed to emerge at approximately, respectively, 2 and 5 years after the start of preoperative treatment. We further explored the data with the aim of refining our understanding of the long-term results. PATIENTS AND METHODS: Data of 785 of the 1,011 randomly assigned patients who whose disease was M0 at curative surgery were used. Using meta-analytic methods, we investigated the homogeneity of the effect of adjuvant CT on the time to relapse or death after surgery (disease-free survival [DFS]) and survival in patient subgroups. RESULTS: Although there was no statistically significant impact of adjuvant CT on DFS for the whole group (P > .5), the treatment effect differed significantly between the ypT0-2 and the ypT3-4 patients (heterogeneity P = .009): only the ypT0-2 patients seemed to benefit from adjuvant CT (P = .011). The same pattern was observed for overall survival. CONCLUSION: Exploratory analyses suggest that only good-prognosis patients (ypT0-2) benefit from adjuvant CT. This could explain why, in the whole group, the progression-free and overall survival diverged only after the poor-prognosis patients (ypT3-4) had experienced treatment failure. Patients in whom no downstaging was achieved did not benefit. This also suggests that the same prognostic factors may drive both tumor sensitivity for the primary treatment and long-term clinical benefit from further adjuvant CT.

Preoperative radiotherapy in elderly patients with rectal cancer.

PURPOSE: We performed a retrospective analysis in order to evaluate the compliance with preoperative radiotherapy in patients aged>or=70 with locally advanced resectable rectal cancer, and to evaluate the influence of comorbidities on treatment tolerance and oncological results. METHODS: From March 1984 to December 2000, 95 patients with T3-T4 N0 M0 rectal cancer received a preoperative radiotherapy in 2 radiotherapy departments. Nineteen patients received concomitant chemotherapy. RESULTS: All patients completed the radiation schedule. Six patients suffered grade 3 acute WHO toxicity. Surgical resection was performed in 87 patients. There were 3 post-operative deaths. Analysis of peri-operative complications showed thromboembolism (4.9%), ileus (9.8%) and diarrhoea (6.1%). After a median follow-up of 29 months, the 3- and 5-year overall survival rates were 65% and 49% respectively. In univariate analysis, a tumour located in the mid part of the rectum, a radiation dose less than 40 Gy, the absence of chemotherapy were significantly associated with a poor prognosis. There was a trend to a better survival for patients with a Charlson score of 0 (P=0.0584). In multivariate analysis, only initial WHO performance status was significant. CONCLUSIONS: Compliance with preoperative radiotherapy is good in elderly patients. Toxicity rates are similar to those described in randomised trials in which only younger patients were included. Initial WHO performance status