Clinical Progression-free Survival Research Articles

Phase II Trial of Sunitinib for the Therapy of Progressive Metastatic Castration-Refractory Prostate Cancer After Previous Docetaxel Chemotherapy

Effective options are lacking for progressive castration-refractory prostate cancer (CRPC) after conventional chemotherapy. Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor that is approved multinationally for renal cell carcinoma and gastrointestinal stromal tumors. A phase II trial was conducted to examine the efficacy and toxicities of sunitinib in metastatic CRPC progressing after 1-2 previous chemotherapy regimens including docetaxel. The primary objective was clinical progression-free survival (PFS) with a 12-week PFS ≤ 30% assumed to be of interest. Secondary objectives included prostate-specific antigen (PSA) response, modulation of PSA kinetics, objective response, quality of life, pain, survival, and toxicities. Sunitinib 50 mg daily was administered orally on days 1-28 of each 6-week cycle. Patients were treated to a maximum of 8 cycles or until clinically progressive disease or intolerable toxicity.

Azacitidine for castration-resistant prostate cancer progressing on combined androgen blockade

5172 Background: Vidaza (azacitidine, Pharmion Corp), a demethylating agent that activates genes repressed by promoter methylation, may induce responses in malignancies. Preclinically, demethylating agents reverse resistance of prostate cancer to androgen ablation. We conducted a phase II trial of azacitidine in CRPC (castration-resistant prostate cancer) progressing on CAB (combined androgen blockade). Methods: Eligibility criteria included chemonaïve metastatic or nonmetastatic CRPC on CAB and PSA-doubling time (DT) <3 months. The primary endpoint was modulation of PSADT; secondary objectives were PSA response, clinical progression-free survival (PFS), survival, and toxicities. Correlation of biologic activity [fetal hemoglobin (HbF), plasma DNA methylation] with outcomes was done. CAB was continued; azacitidine 75 mg/m2 SC was given Days 1–5 of each 28-day cycle up to 12 cycles or until clinical progression/toxicities. Results: The accrual of 36 patients (pts) is complete, and 20 are currently evaluable for PSADT. Most pts (80.6%) had metastases. A PSADT of >3 months was attained in 8 pts (40%) and 7 other pts exhibited some slowing of PSADT compared to baseline. Overall PSADT post-therapy was significantly prolonged compared to baseline (P<0.01). No PSA declines were observed. The median PFS was 13.3 weeks (95% CI: 11.3, 16.4), while 7 of 36 pts (intent-to-treat analysis) had prolonged PFS ranging from 16- 58 weeks. Grade 3 toxicities (no Grade 4) were fatigue (9%), and neutropenia (6%), with 2 pts discontinuing due to toxicities. Increases in HbF were noted in 8 pts. A linear mixed effect model fit for the average methylation level suggested a significant decreasing trend of average LINE methylation in plasma DNA over time. Correlation of biologic activity with outcomes is ongoing. Conclusions: Azacitidine exhibited biologic activity (increases in HbF, decreased plasma DNA methylation), and may have antitumor activity in progressive chemonaïve CRPC (prolongation of PSADT and PFS in selected patients). The toxicity profile was favorable. Updated clinical data and correlative studies from all pts will be presented. These data may warrant the further development of azacitidine for CRPC. This research was supported, in part, by a research grant from Pharmion Corp. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ASCO Career Development Award

Sunitinib malate for metastatic castration resistant prostate cancer following docetaxel-based chemotherapy

5157 Background: Sunitinib malate is a multitargeted tyrosine kinase inhibitor approved multinationally for renal cell carcinoma and gastrointestinal stromal tumors. Effective options are lacking for progressive CRPC (castration-resistant prostate cancer) following conventional chemotherapy. This phase II trial was conducted to examine the efficacy and toxicity of sunitinib in metastatic CRPC progressing after prior chemotherapy. Methods: Key inclusion: histologically confirmed adenocarcinoma (metastatic stage IV), clinical or PSA progression, currently on androgen ablation treatment, with 1- 2 prior chemotherapy regimens including docetaxel. Other standard (drug specific) inclusion/exclusion criteria applied. The primary objective was clinical progression-free survival (PFS) with a 12-week PFS >30% as a goal. Secondary objectives: PSA response, objective response, quality of life, pain, survival, and toxicities. Sunitinib 50 mg/day was administered orally 4 weeks on / 2 weeks off in 6-week cycles. Patients (pts) were treated to a maximum of 8 cycles or until clinically progressive disease or intolerable toxicity. A planned interim analysis of the first 19 pts is presented here; accrual goals (n=36) have been met. Results: The median age was 69 years. The median clinical PFS (as per RECIST, bone events, pain, obstruction, ECOG) for these pts was 2.8 months (95% CI, 2.2, 6.1) with a 12-week PFS attained in 48.3%. A 50% PSA response was seen in 1 pt, and 30% PSA response was seen in 3 pts, with an additional 2 pts with unconfirmed 30% PSA responses. Grade 3–4 therapy related toxicities were infrequent with only Grade 3 anemia occurring in 2 pts; 7 pts died due to disease progression with 2 deaths deemed possibly related to sunitinib (non- neutropenic sepsis and hemorrhagic stroke, n=1 each). Conclusions: Single-agent sunitinib malate demonstrated significant antitumor activity with manageable toxicities in men with metastatic CRPC that had progressed following 1–2 prior regimens including docetaxel. Accrual is complete and final efficacy and toxicity data on all pts will be presented. These data warrant further evaluation of sunitinib in metastatic CRPC. Supported, in part, by a grant from Pfizer, Inc., New York, NY. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer, GlaxoSmithKline, Pfizer Oncology, Wyeth Bayer, GlaxoSmithKline, Pfizer Oncology, Wyeth Bayer, GlaxoSmithKline, Pfizer Oncology, Wyeth

External-Beam Radiotherapy for Localized or Locally Advanced Prostate Cancer in Japan: A Multi-Institutional Outcome Analysis

The outcomes of patients with localized or locally advanced prostate cancer treated with external-beam radiotherapy are not well known in Japan. Thirty-four institutions combined data on 679 patients with localized or locally advanced prostate cancer treated with a total dose >/=60 Gy between 1995 and 2002. With a median follow-up of 46 months, the 5-year overall, clinical progression-free, and biochemical relapse-free survival rate were 93.0, 95.3 and 71.9% for all patients, respectively. The 5-year progression-free, and biochemical relapse-free survival rates according to the risk group were 100%, 90.8% in the low-risk group, 98.3%, 75.7% in the intermediate-risk group and 93.6%, 67.6% in the high-risk group, respectively. The multivariate analysis for biochemical relapse-free survival revealed that prostate-specific antigen (relative risk, 1.002; 95% CI, 1.001-1.003; P = 0.0041), Gleason score (relative risk, 1.166; 95% CI, 1.046-1.302; P = 0.0055), T classification (relative risk, 2.897; 95% CI, 1.999-4.230; P = 0.0000), pelvic irradiation (relative risk, 2.042; 95% CI, 1.328-3.273; P = 0.0008), and androgen abletion (relative risk, 0.321; 95% CI, 0.240-0.427; P = 0.0000) were significant prognostic factors. Only 1.1% of patients experienced late morbidity of Grade 3. Radiotherapy for prostate cancer seemed to be effective, with little risk of normal tissue complications.

GAMMA KNIFE SURGERY FOR LOW-GRADE GLIOMAS

Data regarding the long-term efficacy of Gamma knife surgery on a large series of patients with low-grade gliomas is lacking. We aimed to review the outcome of patients with low-grade gliomas undergoing Gamma knife surgery at the Lars Leksell Gamma Knife Center at the University of Virginia to clarify its role in the management of these lesions. A retrospective review of 49 patients treated between 1989 and 2003 was conducted. The median follow up was 63 months. Gamma knife surgery was generally performed for tumors in eloquent brain, residual tumor post-surgery or for late progression after surgery. Median clinical progression free survival was 44 months and median radiological progression free survival was 37 months. Five-year radiological progression free survival was 37% while clinical progression free survival was 41%. Mortality due to tumor progression occurred in 7 patients (14%). Complete radiological remission was seen in 14 patients (29%). Complications due to Gamma surgery were seen in 4 patients (8%). Of these, two resolved without sequelae, one required surgery for neurological decline and associated radiation induced changes, and one patient suffered a permanent neurological deficit from treatment. Gamma knife radiosurgery is a safe treatment for low-grade gliomas and may be considered in patients with residual or recurrent disease.

Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: Part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5

To compare parenteral estrogen therapy in the form of high-dose polyestradiol phosphate (PEP; Estradurin) with combined androgen deprivation (CAD) in the treatment of prostate cancer patients with skeletal metastases. The aim of the study was to compare anticancer efficacy and adverse events, especially cardiovascular events. In total, 910 eligible patients with T0-4, NX, M1, G1-3 prostate cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were randomized to treatment with either PEP 240 mg i.m. twice a month for 2 months and thereafter monthly, or flutamide (Eulexin) 250 mg t.i.d. per os in combination with either triptorelin (Decapeptyl) 3.75 mg i.m. per month or on an optional basis bilateral orchidectomy. At this final evaluation of the trial 855 of the 910 patients were dead. There was no difference between the treatment groups in terms of biochemical or clinical progression-free survival or in overall or disease-specific survival. There was no difference in cardiovascular mortality, but a significant increase in non-fatal cardiovascular events in the PEP arm (p<0.05) predominantly caused by an increase in ischemic heart and heart decompensation events. There were 18 grave skeletal events in the CAD group but none in the PEP group (p=0.001). PEP has an anticancer efficacy equal to CAD and does not increase cardiovascular mortality in metastasized patients, but carries a significant risk of non-fatal cardiovascular events, which should be balanced against the skeletal complications in the CAD group. It is feasible to use Estradurin in the primary or secondary endocrine treatment of metastasized patients without prominent cardiac risk factors and especially those with osteoporosis.

Résultats préliminaires de l'essai EORTC 22911 : prostatectomie radicale suivie ou non de radiothérapie postopératoire dans les cancers de la prostate à haut risque de récidive

Purpose Local failure after radiotherapy can arise with cancer extending beyond the capsule and/or involvement of seminal vesicles or positive surgical margins. Methodology After undergoing radical prostatectomy 1005 patients were randomly assigned (1999–2001) to a wait and see policy or an immediate postoperative irradiation (60 Gy delivered over 6 weeks); eligible patients had pN0 M0 tumors and one or more pathological risk factors mentioned above. The main end-point was 5-year biochemical progression free survival. Results After a median follow-up of 5-year biochemical progression free survival was significantly improved in the irradiated group (74%, 98% CI: 68.7–79.3 vs 52.6%, 98% CI: 46.6–58.5; P < 0.0001) Clinical progression free survival was also significantly improved ( P < 0.0009). The cumulative rate of loco-regional failure was also significantly improved ( P < 0.0009). Grade 2 or 3 late effects were significantly more frequent in the postoperative irradiation group ( P = 0.0005), but severe 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 = 0.07). Conclusion Immediate external irradiation after radical prostatectomy improves biochemical progression free survival and local control in patients with positive surgical margin or pT3 prostate cancer who are at high risk of progression. Further follow-up is needed to assess the impact on overall survival.

Prostate Cancer-Specific Survival and Clinical Progression-Free Survival in Men with Prostate Cancer Treated Intermittently with Testosterone Inactivating Pharmaceuticals

More than 85% of men with prostate cancer die of other causes. An effective method is needed to distinguish fatal forms of prostate cancer from benign variants. We performed a retrospective chart review from a medical oncology practice specializing in prostate cancer. All men with negative bone scans, prostate-specific antigen (PSA) level less than 100 ng/mL, adequate records for review, and who started taking testosterone inactivating pharmaceutical (TIP) agents before January 2000 were included in the study. Six factors were evaluated as potential predictors of prostate cancer-specific mortality: PSA nadir greater than 0.05 ng/mL while taking TIP, PSA doubling time of less than 12 months, Gleason score, stage, baseline PSA level greater than 20 ng/mL, and age. The study criteria were met by 160 men. The median follow-up was 10 years. The median age, PSA level, PSA nadir, and PSA doubling time was 65.6 years, 9.6 ng/mL, 0.03 ng/mL, and 10 months, respectively. Of the 160 men, 39 died of prostate cancer. Death from prostate cancer was far more common (78% versus 11%) and accelerated (median of 4 years versus 7 years) for men with a PSA nadir greater than 0.05 ng/mL than for those with a lower nadir. Multivariate Cox regression analysis indicated that the hazard ratio for prostate cancer-specific mortality in men with a PSA nadir greater than 0.05 ng/mL was 11.6 (P <0.0001). The hazard ratio for men with a PSA doubling time of less than 12 months was 2.9 (P = 0.04). Gleason score, stage, baseline PSA level greater than 20 ng/mL, and age were not statistically significant. Of the factors studied, the PSA nadir while taking a TIP was the best predictor of prostate cancer-specific mortality.

10-Year Survival and Quality of Life in Patients With High-Risk PN 0 Prostate Cancer Following Definitive Radiotherapy

To evaluate long-term overall survival (OS), cancer-specific survival (CSS), clinical progression-free survival (cPFS), and health-related quality of life (HRQoL) following definitive radiotherapy (RT) given to T(1-4p)N(0)M(0) prostate cancer patients provided by a single institution between 1989 and 1996. We assessed outcome among 203 patients who had completed three-dimensional conformal RT (66 Gy) without hormone treatment and in whom staging by lymphadenectomy had been performed. OS was compared with an age-matched control group from the general population. A cross-sectional, self-report survey of HRQoL was performed among surviving patients. Median observation time was 10 years (range, 1-16 years). Eighty-one percent had high-risk tumors defined as T(3-4) or Gleason score (GS) > or =7B (4+3). Among these, 10-year OS, CSS, and cPFS rates were 52%, 66%, and 39%, respectively. The corresponding fractions in low-risk patients (T(1-2) and GS < or =7A [3+4]) were 79%, 95%, and 73%, respectively. Both CSS and cPFS were predicted by GS and T-classification; OS was associated with GS only. High-risk, but not low-risk, patients had reduced OS compared with the general population (p < 0.0005). When pelvis-related side effects were included in multivariate analyzes together with physical function and pain, sexual, urinary, and bowel function were not independently associated with self-reported global quality of life. Despite surgically proven (p)N(0), RT with dosage <70 Gy as monotherapy does not give satisfactory CSS rates after 10 years in patients with T(3-4) or GS > or =7B.

Concomitant and adjuvant androgen deprivation (ADT) with external beam irradiation (RT) for locally advanced prostate cancer: 6 months versus 3 years ADT—Results of the randomized EORTC Phase III trial 22961

5014 Background: After EORTC trial 22863, 3 years of endocrine treatment has become standard adjuvant treatment to RT for locally advanced prostate cancer. EORTC 22961 tests if similar survival can be achieved in patients who underwent EBRT (to 70 Gy) and 6 months of combined ADT without further ADT (SADT arm) as in patients with 2.5 years of further treatment with luteinizing hormone-releasing hormone agonist monotherapy (LADT arm). Methods: Eligible patients had T1c-2b N1–2 or pN1–2, or T2c-4 N0–2 (UICC 1992) M0 prostate cancer with PSA &lt;150ng/ml. Non-inferior survival was defined as a morality hazard ratio (HR) = 1.35 for SADT vs LADT. Non inferiority at 80% power and 1-sided a=0.05 required 275 deaths. A stopping boundary was applied at 1-sided a=0.018. Results: 970 patients were randomized (483 SADT and 487 LADT). At 5.2 years median follow-up, 173 patients had died (100 vs 73). An Independent Data Monitoring Committee recommended disclosure of results based on an interim analysis showing futility. Patient characteristics were well balanced: median age 69 years, WHO PS 0 in 83.4%, most patients had T2c-T3 N0 disease. Progression (mostly biochemical and/or bone progression) occurred in 220 cases (159 on SADT vs 61 on LADT) and was treated by secondary hormonal manipulation. The 5-year overall survival rate was 85.3% on LADT and 80.6% on SADT (HR=1.43, 96.4% CI: 1.04–1.98), and failed to prove non-inferiority. The 5-year clinical progression-free survival rate was 81.8% on LADT versus 68.9% on SADT arm and the 5-year biochemical progression-free survival rate was 78.3% on LADT versus 58.9% on SADT, indicating inferiority of SADT with HR=1.93 and HR=2.29, respectively. Conclusions: The study was designed to demonstrate non-inferior survival with 6 months ADT compared to 3 years adjuvant ADT after irradiation for patients with locally advanced prostate cancer, but observed survival data indicate that non-inferiority cannot be confirmed. Progression-free survival was also shorter on SADT. No significant financial relationships to disclose.

Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial

In men with localised prostate cancer, conformal radiotherapy (CFRT) could deliver higher doses of radiation than does standard-dose conventional radical external-beam radiotherapy, and could improve long-term efficacy, potentially at the cost of increased toxicity. We aimed to present the first analyses of effectiveness from the MRC RT01 randomised controlled trial. The MRC RT01 trial included 843 men with localised prostate cancer who were randomly assigned to standard-dose CFRT or escalated-dose CFRT, both administered with neoadjuvant androgen suppression. Primary endpoints were biochemical-progression-free survival (bPFS), freedom from local progression, metastases-free survival, overall survival, and late toxicity scores. The toxicity scores were measured with questionnaires for physicians and patients that included the Radiation Therapy Oncology Group (RTOG), the Late Effects on Normal Tissue: Subjective/Objective/Management (LENT/SOM) scales, and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI) scales. Analysis was done by intention to treat. This trial is registered at the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN47772397. Between January, 1998, and December, 2002, 843 men were randomly assigned to escalated-dose CFRT (n=422) or standard-dose CFRT (n=421). In the escalated group, the hazard ratio (HR) for bPFS was 0.67 (95% CI 0.53-0.85, p=0.0007). We noted 71% bPFS (108 cumulative events) and 60% bPFS (149 cumulative events) by 5 years in the escalated and standard groups, respectively. HR for clinical progression-free survival was 0.69 (0.47-1.02; p=0.064); local control was 0.65 (0.36-1.18; p=0.16); freedom from salvage androgen suppression was 0.78 (0.57-1.07; p=0.12); and metastases-free survival was 0.74 (0.47-1.18; p=0.21). HR for late bowel toxicity in the escalated group was 1.47 (1.12-1.92) according to the RTOG (grade >/=2) scale; 1.44 (1.16-1.80) according to the LENT/SOM (grade >/=2) scales; and 1.28 (1.03-1.60) according to the UCLA PCI (score >/=30) scale. 33% of the escalated and 24% of the standard group reported late bowel toxicity within 5 years of starting treatment. HR for late bladder toxicity according to the RTOG (grade >/=2) scale was 1.36 (0.90-2.06), but this finding was not supported by the LENT/SOM (grade >/=2) scales (HR 1.07 [0.90-1.29]), nor the UCLA PCI (score >/=30) scale (HR 1.05 [0.81-1.36]). Escalated-dose CFRT with neoadjuvant androgen suppression seems clinically worthwhile in terms of bPFS, progression-free survival, and decreased use of salvage androgen suppression. This additional efficacy is offset by an increased incidence of longer term adverse events.

Adjuvant Radiotherapy Results following Radical Prostatectomy—A Critical Review

Objectives The author attempts to better define the treatment of patients with locally advanced prostate cancer following radical prostatectomy. Methods The data of the most recent series in the international literature have been analysed. Results The risk of biochemical or clinical relapse in the literature is not clear. Recently, two randomised phase 3 trials have been published showing a statistical significant benefit of adjuvant irradiation with respect to biochemical and clinical progression-free survival. Toxicity of adjuvant radiotherapy was moderate in these studies. However, the range of patients with pT3 disease is large (extracapsular extension with/without positive margins, positive margins only, and seminal vesicle invasion), and the challenging question now is whether we can find a subgroup of patients with pT3 disease who will benefit most from adjuvant irradiation to prevent overtreatment for a considerable number of patients, and to reduce toxicity and costs. Conclusions Instead of offering all patients immediate adjuvant treatment, patients with minor risk of relapse could be monitored carefully and offered salvage radiotherapy once biochemical relapse is observed.

Statins, Especially Atorvastatin, May Favorably Influence Clinical Presentation and Biochemical Progression-Free Survival After Brachytherapy for Clinically Localized Prostate Cancer

Statins, Especially Atorvastatin, May Favorably Influence Clinical Presentation and Biochemical Progression-Free Survival After Brachytherapy for Clinically Localized Prostate Cancer

Intensity-modulated radiotherapy for pituitary adenomas: The preliminary report of the Cleveland Clinic experience

Intensity-modulated radiotherapy (IMRT) is being increasingly used for the treatment of pituitary adenomas. However, there have been few published data on the short- and long-term outcomes of this treatment. This is the initial report of the Cleveland Clinic's experience. Between February 1998 and December 2003, 34 patients with pituitary adenomas were treated with IMRT. A retrospective chart review was conducted for data analysis. With a median follow-up of 42.5 months, the treatment has proven to be well tolerated, with performance status remaining stable in 90% of patients. Radiographic local control was 89%, and among patients with secretory tumors, 100% had a biochemical response. Only 1 patient required salvage surgery for progressive disease, giving a clinical progression free survival of 97%. The only patient who received more than 46 Gy experienced optic neuropathy 8 months after radiation. Smaller tumor volume significantly correlated with subjective improvements in nonvisual neurologic complaints (p = 0.03), and larger tumor volume significantly correlated with subjective worsening of visual symptoms (p = 0.05). New hormonal supplementation was required for 40% of patients. Younger patients were significantly more likely to require hormonal supplementation (p = 0.03). Intensity-modulated radiation therapy is a safe and effective treatment for pituitary adenomas over the short term. Longer follow-up is necessary to determine if IMRT confers any advantage with respect to either tumor control or toxicity over conventional radiation modalities.

Postoperative radiotherapy after radical prostatectomy: A randomised controlled trial (EORTC trial 22911): Bolla M, van Poppel H, Collette L, van Cangh P, Vekemans K, Da Pozzo L, de Reijke TM, Verbaeys A, Bosset J-F, van Velthoven R, Maréchal J-M, Scalliet P, Haustermans K, Piérart M, European Organization for Research and Treatment of Cancer, Department of Radiation Oncology, Centre Hospitalier Universitaire

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. 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. 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). 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): Collette L, van Poppel H, Bolla M, van Cangh P, Vekemans K, Da Pozzo L, de Reijke TM, Verbaeys A, Bosset J-F, Piérart M, European Organisation for Research and Treatment of Cancer (EORTC) Radiotherapy and Genito-urinary Groups, European Organisation for

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.

Outcome of Surgery for Clinical Unilateral T3a Prostate Cancer: A Single-Institution Experience

ObjectivesThe optimal management of locally advanced prostate cancer (cT3) is still a matter of debate. The objective of this study is to present 10-year outcomes of radical prostatectomy (RP) in unilateral cT3a disease. Patients and methodsBetween 1987 and 2004, 2273 patients underwent RP at our institution. Two hundred and thirty-five (10.3%) patients were assessed as unilateral cT3a disease by digital rectal examination. Thirty-five patients who received neoadjuvant treatment before surgery were excluded from further analysis. Mean follow-up was 70.6 months. Kaplan-Meier survival analysis was used to calculate the biochemical progression-free survival (BPFS), clinical progression-free survival (CPFS), cancer-specific survival (CSS), and overall survival (OS) rates. Cox uni- and multivariate regression analyses were used to identify predictive factors in BPFS and CPFS. ResultsClinical overstaging (pT2) occurred in 23.5%. One hundred and twelve (56%) patients received adjuvant or salvage therapy. OS at 5 and 10 years was 95.9% and 77.0%, respectively, and CSS was 98.7% and 91.6%. BPFS at 5 and 10 years was 59.5% and 51.1%, respectively, and CPFS was 95.9% and 85.4%. Margin status was a significant independent predictor in BPFS; cancer volume was a significant independent predictor in CPFS. ConclusionsClinically advanced prostate cancer is still frequently overstaged. In a well-selected patient group with locally advanced prostate cancer, RP—with adjuvant or salvage treatment when needed—can yield very high long-term cancer control and survival rates. Margin status and cancer volume are significant predictors of outcome after RP.

Disease progression and survival in patients with prostate carcinoma and positive lymph nodes after radical retropubic prostatectomy

To determine disease progression and survival in patients with lymph node-positive prostate carcinoma after ascending radical retropubic prostatectomy (RP) and pelvic lymphadenectomy with different forms of postoperative adjuvant treatment. We analysed 82 patients with lymph node metastases at the time of surgery and who had a RP between 1993 and 2002. Data from clinical records and follow-up questionnaires were used. Overall survival, time to clinical disease progression and time to biochemical progression were used as endpoints to assess the outcome. Clinical progression was defined as documented local recurrence or distant metastases, and biochemical as an increase in prostate-specific antigen (PSA) of > or = 0.4 ng/mL. Variables analysed included PSA level, Gleason score before and after RP, clinical and pathological stage, number of positive lymph nodes and hormone therapy after RP. The statistical assessment included univariate regression analysis, and to analyse the distribution of clinical findings in different groups, Mantel-Haenszel statistics were used to test for differences in the numbers of patients. Survival and progression-free interval were assessed by Kaplan-Meier estimates and differences between groups calculated by log-rank statistics and Cox regression models. The median (range) follow-up was 55 (10-125) months. Adjuvant hormonal treatment was used in 77 patients, five of whom had immediate adjuvant radiotherapy, and nine delayed radiotherapy because of local progression or symptomatic bone metastases; five had no additional treatment. The rates for 5- and 10-year overall survival, clinical progression-free survival and biochemical progression-free survival were 84% and 79%, 83% and 77%, and 70% and 60%, respectively. Ten patients died (12%), eight (10%) of them from the cancer; bone metastases were detected in nine (11%). Local recurrences developed in three (4%) patients, 10 (12%) had a PSA increase of > or = 0.4 ng/mL alone and 58 (71%) had no signs of progression, but two died from other causes. Most patients with prostate cancer who had RP and pelvic lymphadenectomy followed by adjuvant hormone therapy, and who had lymph node metastases at the time of surgery, had excellent overall and progression-free survival in the long term.

Gamma Knife Surgery for Low-Grade Gliomas

Data regarding the long-term efficacy of Gamma knife surgery on a large series of patients with low-grade gliomas is lacking. We aimed to review the outcome of patients with low-grade gliomas undergoing Gamma knife surgery at the Lars Leksell Gamma Knife Center at the University of Virginia to clarify its role in the management of these lesions. A retrospective review of 49 patients treated between 1989 and 2003 was conducted. The median follow up was 63 months. Gamma knife surgery was generally performed for tumors in eloquent brain, residual tumor post-surgery or for late progression after surgery. Median clinical progression free survival was 44 months and median radiological progression free survival was 37 months. Five-year radiological progression free survival was 37% while clinical progression free survival was 41%. Mortality due to tumor progression occurred in 7 patients (14%). Complete radiological remission was seen in 14 patients (29%). Complications due to Gamma surgery were seen in 4 patients (8%). Of these, two resolved without sequelae, one required surgery for neurological decline and associated radiation induced changes, and one patient suffered a permanent neurological deficit from treatment. Gamma knife radiosurgery is a safe treatment for low-grade gliomas and may be considered in patients with residual or recurrent disease.

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 & 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&S group and the Log-rank test for heterogeneity was applied ( α = 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&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.