Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial.

BACKGROUND: Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS: This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS: From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7.0 years (IQR 5.2-8.7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0.78, 95% CI 0.56-1.08; p=0.13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0.54, 95% CI 0.4-0.73, p<0.0001), with 5-year progression-free survival of 47.6% (95% CI 38.8-55.9) in the immediate treatment group and 31.8% (24.2-39.6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION: Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING: Lilly, Canadian Cancer Society Research.

Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911).

BACKGROUND: We report the long-term results of a trial of immediate postoperative irradiation versus a wait-and-see policy in patients with prostate cancer extending beyond the prostate, to confirm whether previously reported progression-free survival was sustained. METHODS: This randomised, phase 3, controlled trial recruited patients aged 75 years or younger with untreated cT0-3 prostate cancer (WHO performance status 0 or 1) from 37 institutions across Europe. Eligible patients were randomly assigned centrally (1:1) to postoperative irradiation (60 Gy of conventional irradiation to the surgical bed for 6 weeks) or to a wait-and-see policy until biochemical progression (increase in prostate-specific antigen >0·2 µg/L confirmed twice at least 2 weeks apart). We analysed the primary endpoint, biochemical progression-free survival, by intention to treat (two-sided test for difference at α=0.05, adjusted for one interim analysis) and did exploratory analyses of heterogeneity of effect. This trial is registered with ClinicalTrials.gov, number NCT00002511. FINDINGS: 1005 patients were randomly assigned to a wait-and-see policy (n=503) or postoperative irradiation (n=502) and were followed up for a median of 10·6 years (range 2 months to 16·6 years). Postoperative irradiation significantly improved biochemical progression-free survival compared with the wait-and-see policy (198 [39·4%] of 502 patients in postoperative irradiation group vs 311 [61·8%] of 503 patients in wait-and-see group had biochemical or clinical progression or died; HR 0·49 [95% CI 0·41-0·59]; p<0·0001). Late adverse effects (any type of any grade) were more frequent in the postoperative irradiation group than in the wait-and-see group (10 year cumulative incidence 70·8% [66·6-75·0] vs 59·7% [55·3-64·1]; p=0.001). INTERPRETATION: Results at median follow-up of 10·6 years show that conventional postoperative irradiation significantly improves biochemical progression-free survival and local control compared with a wait-and-see policy, supporting results at 5 year follow-up; however, improvements in clinical progression-free survival were not maintained. Exploratory analyses suggest that postoperative irradiation might improve clinical progression-free survival in patients younger than 70 years and in those with positive surgical margins, but could have a detrimental effect in patients aged 70 years or older. FUNDING: Ligue Nationale contre le Cancer (Comité de l'Isère, Grenoble, France) and the European Organisation for Research and Treatment of Cancer (EORTC) Charitable Trust.

Intensity-modulated radiation therapy for prostate cancer: late morbidity and results on biochemical control.

PURPOSE: To report on late morbidity and biochemical relapse-free survival (bRFS) after intensity-modulated radiation therapy (IMRT) for prostate cancer. METHODS: Between 1998 and 2005 133 patients were treated with IMRT for T(1-4) N0 M0 prostate cancer. The median follow-up time was 36 months. In a first cohort, patients received a median planning target volume (PTV) dose of 74 Gy with a hard constraint on maximum rectum dose of 72 Gy (74R72, n=51). Later, median PTV and maximum rectum dose were increased to 76 and 74 Gy, respectively (76R74; n=82). We defined low-risk (n=20), intermediate-risk (n=70) and high-risk (n=43) groups. Androgen deprivation was given to patients in the intermediate- and high-risk group. Late gastro-intestinal (GI) and genito-urinary (GU) morbidity and biochemical relapse, in accordance with the ASTRO consensus, were recorded. RESULTS: We observed grade 2 GI (17%) and GU (19%), grade 3 GI (1%) and GU (3%) late toxicities. Except for hematuria, the median duration of side-effects was 6 months. Biochemical relapse-free survival (bRFS) at 3 and 5 years was 88% and 83%, respectively, with a significantly better 3-year bRSF for the 76R74 than for the 74R72 group (p=0.01). Five-year bRFS for patients in the low-risk, intermediate-risk and high-risk group was 100%, 94% and 74%, respectively (p<0.01). CONCLUSION: IMRT for localized or locally advanced prostate cancer combines low morbidity with excellent biochemical control.

Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911).

BACKGROUND: Local failure after prostatectomy can arise in patients with cancer extending beyond the capsule. We did a randomised controlled trial to compare radical prostatectomy followed by immediate external irradiation with prostatectomy alone for patients with positive surgical margin or pT3 prostate cancer. METHODS: After undergoing radical retropubic prostatectomy, 503 patients were randomly assigned to a wait-and-see policy, and 502 to immediate postoperative radiotherapy (60 Gy conventional irradiation delivered over 6 weeks). Eligible patients had pN0M0 tumours and one or more pathological risk factors: capsule perforation, positive surgical margins, invasion of seminal vesicles. Our revised primary endpoint was biochemical progression-free survival. Analysis was by intention to treat. FINDINGS: The median age was 65 years (IQR 61-69). After a median follow-up of 5 years, biochemical progression-free survival was significantly improved in the irradiated group (74.0%, 98% CI 68.7-79.3 vs 52.6%, 46.6-58.5; p<0.0001). Clinical progression-free survival was also significantly improved (p=0.0009). The cumulative rate of locoregional failure was significantly lower in the irradiated group (p<0.0001). Grade 2 or 3 late effects were significantly more frequent in the postoperative irradiation group (p=0.0005), but severe toxic toxicity (grade 3 or higher) were rare, with a 5-year rate of 2.6% in the wait-and-see group and 4.2% in the postoperative irradiation group (p=0.0726). INTERPRETATION: Immediate external irradiation after radical prostatectomy improves biochemical progression-free survival and local control in patients with positive surgical margins or pT3 prostate cancer who are at high risk of progression. Further follow-up is needed to assess the effect on overall survival.

Patients at high risk of progression after radical prostatectomy: do they all benefit from immediate post-operative irradiation? (EORTC trial 22911).

EORTC trial 22911 demonstrated that immediate postoperative irradiation significantly improved biochemical failure free survival (BPFS) compared to wait-and-see (W and S) until relapse in patients with pT2-3 tumours and pathological risk factors after radical prostatectomy. In this study, we have investigated the heterogeneity of the treatment benefit across defined subgroups of patients. Data from 972 patients were used. A risk model was developed in the W and S group and the Log-rank test for heterogeneity was applied (alpha=0.05). Positive surgical margin (SM+), seminal vesicle invasion (SV+), WHO differentiation grade, pre- and post-operative PSA were independent predictors for BPFS in the W and S group. Men with SV+ were at higher risk of relapse whereas those with SM+ but no capsule infiltration (ECE-) did not seem to differ from those with SM-ECE+ or with SM+ECE+. Postoperative irradiation improved biochemical progression-free survival in all patient groups. Longer follow-up is needed to assess the endpoint of clinical progression-free survival.

Intensity-modulated radiotherapy as primary treatment for prostate cancer: acute toxicity in 114 patients.

INTRODUCTION: Dose escalation improves local control in prostate cancer. At Ghent University Hospital, intensity-modulated radiotherapy (IMRT) is used to increase the dose to the prostate and/or seminal vesicles. We report on acute toxicity in 114 patients who received IMRT for prostate cancer. METHODS AND MATERIALS: Intensity-modulated radiotherapy was initiated after approval of our ethics committee. A class solution was used to plan all cases. Three beams (gantry 0 degrees , 116 degrees , and 244 degrees ) and anatomy-based segmentation were used to create an intensity-modulated dose distribution. Maximal rectal dose was set at 2 Gy per fraction. Detailed dose-volume histograms for all relevant structures were present. For all patients, we determined the pretreatment morbidity by a detailed preradiotherapy, in-house developed symptom scale. All patients were treated with 18 MV photons of an Elekta linear accelerator. Patients were seen on a weekly basis during treatment, and 1 month (M1) and 3 months (M3) thereafter. The registration of acute toxicity was standardized by a fixed questionnaire. The Radiation Therapy Oncology Group (RTOG) toxicity scale served as a basis, but additional symptoms, such as rectal blood loss, urgency, and incontinence, were scored as well. RESULTS: All 114 IMRT plans were delivered successfully without any interruption or technical problem. Daily treatment time was always less than 8 min and less than 6 min in 90% of the cases. Grade 1 and Grade 2 gastrointestinal (GI) toxicities were observed in 44% and 29% of the patients, respectively, during the whole period. If only the RTOG scale was used, Grade 1 and Grade 2 GI toxicities were noted in 39% and 27% of the patients, respectively, leaving 34% free of acute RTOG-scaled toxicity. Grade 3 genitourinary (GU) toxicity was seen in 8 patients (7%), all but 1 during treatment. Grade 2 and Grade 1 GU toxicities were seen in 36% and 47% of the patients, respectively, leaving only 10% free of acute GU toxicity. DISCUSSION: Anatomy-based IMRT to treat prostate cancer is incorporated into our daily routine without any problem. Acute toxicity is very low. Most of the recorded symptoms decrease over time, except for GI urgency and incontinence. The incorporation of additional symptoms makes the scoring more detailed.

Combined magnetic resonance imaging and spectroscopy in the assessment of high grade prostate carcinoma in patients with elevated PSA: a single-institution experience of 356 patients.

PURPOSE: To assess the ability of combined whole-prostate magnetic resonance imaging and magnetic resonance spectroscopy imaging (MRI+MRSI) to predict the presence or absence of high grade (Gleason 4+3 or higher) prostate carcinoma in men with elevated PSA. MATERIALS AND METHODS: Between March 2002 and September 2007, 356 subjects (mean serum PSA 11.5 ng/ml, range 0.4-133.0 ng/ml) were examined with fast-T2-weighted magnetic resonance imaging (MRI) and 3D-magnetic resonance spectroscopy imaging (MRSI) on a 1.5T scanner. Prostate cancer was histopathologically proven in 220 patients (41 with high grade and 179 with lower grade cancer) and non-evidence of cancer was determined after at least 12 months (mean 21 months) clinical follow-up in 136 subjects. The sensitivity, false positive rate, and negative predictive value of MRI+MRSI were calculated using histopathology and follow-up results as reference standard. RESULTS: MRI+MRSI had a significantly higher sensitivity for high grade tumors (92.7%) than for lower grade tumors (67.6%), and was false positive in only 7.4% of patients with non-evidence of prostate cancer. For exclusion of a high grade tumor, MRI+MRSI had a negative predictive value of 98.4%. CONCLUSIONS: MRI+MRSI holds great potential for predicting presence or absence of high grade tumors in men with elevated PSA. This can be important in the selection of patients for active surveillance, or in the decision to rebiopsy patients with prior negative biopsies.