Standardized technique for ejaculation preservation during prostatic endoscopic ablative surgery.

PURPOSE: Ejaculatory dysfunction is the most common side effect of benign prostatic hyperplasia surgery. Modified techniques have emerged with the aim of preserving antegrade ejaculation without compromising obstruction relief. None are standardized or validated. The PARTURP study is a randomized study investigating partial versus complete prostate resection. We conducted an investigator consensus meeting to define the ideal surgical technique to achieve both correct obstruction relief with ejaculation preservation. METHODS: An expert consensus meeting involving all investigators of the PARTURP study took place to define a common technique using the nominal group methodology. The objectives were to define the areas to be resected and the areas to be preserved; to define the criteria for proper obstruction relief; to define the criteria for proper ejaculation preservation. RESULTS: All investigators (n = 15) attended the consensus meeting, and agreement between all the participants was obtained. The anatomical landmarks to be preserved are located around the verumontanum and along the posterior part of the prostatic urethra. These structures must be preserved up to 2 cm from the verumontanum. The participants agreed on the need to preserve the urethral mucosa in all the areas to be preserved and to reach the enucleation plane in the areas of resection. CONCLUSIONS: Anatomical landmarks for ejaculation-sparing surgery have been defined by the investigators of the PARTURP randomized study. These landmarks will be used during the study, and the clinical outcomes of this ejaculation-sparing technique will be compared with complete resection with up to 3 years follow-up.

Best Current Practice and Research Priorities in Active Surveillance for Prostate Cancer-A Report of a Movember International Consensus Meeting.

BACKGROUND: Active surveillance (AS) is recommended for low-risk and some intermediate-risk prostate cancer. Uptake and practice of AS vary significantly across different settings, as does the experience of surveillance-from which tests are offered, and to the levels of psychological support. OBJECTIVE: To explore the current best practice and determine the most important research priorities in AS for prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A formal consensus process was followed, with an international expert panel of purposively sampled participants across a range of health care professionals and researchers, and those with lived experience of prostate cancer. Statements regarding the practice of AS and potential research priorities spanning the patient journey from surveillance to initiating treatment were developed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Panel members scored each statement on a Likert scale. The group median score and measure of consensus were presented to participants prior to discussion and rescoring at panel meetings. Current best practice and future research priorities were identified, agreed upon, and finally ranked by panel members. RESULTS AND LIMITATIONS: There was consensus agreement that best practice includes the use of high-quality magnetic resonance imaging (MRI), which allows digital rectal examination (DRE) to be omitted, that repeat standard biopsy can be omitted when MRI and prostate-specific antigen (PSA) kinetics are stable, and that changes in PSA or DRE should prompt MRI ± biopsy rather than immediate active treatment. The highest ranked research priority was a dynamic, risk-adjusted AS approach, reducing testing for those at the least risk of progression. Improving the tests used in surveillance, ensuring equity of access and experience across different patients and settings, and improving information and communication between and within clinicians and patients were also high priorities. Limitations include the use of a limited number of panel members for practical reasons. CONCLUSIONS: The current best practice in AS includes the use of high-quality MRI to avoid DRE and as the first assessment for changes in PSA, with omission of repeat standard biopsy when PSA and MRI are stable. Development of a robust, dynamic, risk-adapted approach to surveillance is the highest research priority in AS for prostate cancer. PATIENT SUMMARY: A diverse group of experts in active surveillance, including a broad range of health care professionals and researchers and those with lived experience of prostate cancer, agreed that best practice includes the use of high-quality magnetic resonance imaging, which can allow digital rectal examination and some biopsies to be omitted. The highest research priority in active surveillance research was identified as the development of a dynamic, risk-adjusted approach.

Molecular biomarkers in the context of focal therapy for prostate cancer: recommendations of a Delphi Consensus from the Focal Therapy Society.

BACKGROUND: Focal therapy (FT) for prostate cancer (PCa) is promising. However, long-term oncological results are awaited and there is no consensus on follow-up strategies. Molecular biomarkers (MB) may be useful in selecting, treating and following up men undergoing FT, though there is limited evidence in this field to guide practice. We aimed to conduct a consensus meeting, endorsed by the Focal Therapy Society, amongst a large group of experts, to understand the potential utility of MB in FT for localized PCa. METHODS: A 38-item questionnaire was built following a literature search. The authors then performed three rounds of a Delphi Consensus using DelphiManager, using the GRADE grid scoring system, followed by a face-to-face expert meeting. Three areas of interest were identified and covered concerning MB for FT, 1) the current/present role; 2) the potential/future role; 3) the recommended features for future studies. Consensus was defined using a 70% agreement threshold. RESULTS: Of 95 invited experts, 42 (44.2%) completed the three Delphi rounds. Twenty-four items reached a consensus and they were then approved at the meeting involving (N.=15) experts. Fourteen items reached a consensus on uncertainty, or they did not reach a consensus. They were re-discussed, resulting in a consensus (N.=3), a consensus on a partial agreement (N.=1), and a consensus on uncertainty (N.=10). A final list of statements were derived from the approved and discussed items, with the addition of three generated statements, to provide guidance regarding MB in the context of FT for localized PCa. Research efforts in this field should be considered a priority. CONCLUSIONS: The present study detailed an initial consensus on the use of MB in FT for PCa. This is until evidence becomes available on the subject.

Radical Prostatectomy after Vascular Targeted Photodynamic Therapy with Padeliporfin: Feasibility, and Early and Intermediate Results.

PURPOSE: Vascular targeted photodynamic therapy with TOOKAD® is a new therapeutic option for localized prostate cancer management. The objectives of this study were to assess the feasibility of radical prostatectomy after vascular targeted photodynamic therapy and describe functional and oncologic outcomes. MATERIALS AND METHODS: We retrospectively included in study 45 patients who underwent salvage radical prostatectomy after vascular targeted photodynamic therapy for recurrent prostate cancer at a total of 14 surgical centers in Europe between October 2008 and March 2017. Of the 42 radical prostatectomies performed 16 were robot-assisted, 6 were laparoscopic and 20 were open surgery. Primary end points were morbidity and technical difficulties. Secondary end points were early and intermediate postoperative functional and oncologic outcomes. RESULTS: Median operative time was 180 minutes (IQR 150-223). Median blood loss was 200 ml (IQR 155-363). According to the surgeons the surgery was easy in 29 patients (69%) and difficult in 13 (31%). Nerve sparing was feasible in 14 patients (33%). Five postoperative complications (12%) were found, including 2 Clavien I, 2 Clavien II and 1 Clavien IIIB complications. Of the cases 13 (31%) were pT3 and 21 (50%) were pT2c. Surgical margins were positive in 13 patients (31%). Prostate specific antigen was undetectable at 6 to 12 months in 37 patients (88%). Nine patients underwent complementary radiotherapy. Four patients had final prostate specific antigen greater than 0.2 ng/ml at a median followup of 23 months (IQR 12-36). At 1 year 27 patients (64%) were completely continent (no pads) and 10 (24%) had low incontinence (1 pad). Four patients (11%) recovered potency without treatment and 23 (64%) recovered potency with appropriate treatment. CONCLUSIONS: Salvage radical prostatectomy after vascular targeted photodynamic therapy treatment was feasible and safe without difficulty for most of the surgeons.

Feasibility, safety, and efficacy of salvage radical prostatectomy after Tookad® Soluble focal treatment for localized prostate cancer.

PURPOSE: To investigate feasibility, safety, and efficacy of salvage radical prostatectomy (RP) for recurrent prostate cancer (PCa) after focal treatment with TOOKAD(®) Soluble vascular-targeted photodynamic therapy (VTP). METHODS: Nineteen patients underwent RP after biopsy-proven PCa post-focal VTP. We reported: operation time, blood loss, transfusion, complications, urethral catheterization time, functional outcomes, and short-term oncologic outcomes. RESULTS: Median age was 64 years (58-70). Median PSA before VTP was 6.30 ng/ml (3.20-9.80). Median delay between VTP and RP was 17 months (8-48). Median blood loss was 400 ml (100-1,000). Median operation time was 150 min (90-210), median urethral catheterization time was 7 days (5-18), and median hospital stay was 7 days (4-21). There was no perioperative mortality. Three patients had related per-operative complications: one pelvic hematoma (150 cc) (Clavien IIIa), one per-operative transfusion (900 cc hemorrhage) (Clavien II), and one superficial wound infection (Clavien I). After a median follow-up of 10 months (1-46), 13 were completely continent (68 %), five needed ≤1 pad/day, and one needed 3 pads/day (Clavien I). Severe erectile dysfunction was observed before and after RP (respectively 8 and 18). Ten patients regained potency with appropriate treatment. Median postoperative PSA was 0.02 ng/ml (<0.01-0.38) and remained undetectable for 16 patients (84 %). Nine patients had positive margins and six underwent complementary radiotherapy. Positive margins were significantly associated with bilateral VTP [risk ratio = 4.3, 95 % confidence interval (1.6-11.7), p = 0.003]. CONCLUSION: Salvage RP after VTP treatment was feasible, safe, and efficient to treat most of the locally recurrent PCa. Short-term oncologic and functional outcomes were promising, but further studies are required.

Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib.

BACKGROUND: Prostate cancer is the second leading cause of male cancer death in developed countries. Although the role of angiogenesis in its progression is well established, the efficacy of anti-angiogenic therapy is not clearly proved. Whether this could depend on differential responses between tumor and normal endothelial cells has not been tested. METHODS: We isolated and characterized three lines of endothelial cells from prostate cancer and we tested the effect of Sunitinib and Sorafenib, and the combined treatment with the anti-androgen Casodex, on their angiogenic functions. RESULTS: Endothelial cells isolated from prostate tumors showed angiogenic properties and expression of androgen and vascular endothelial cell growth factor receptors. Sunitinib affected their proliferation, survival and motility while Sorafenib only showed a minor effect. At variance, Sunitinib and Sorafenib showed similar cytotoxic and anti-angiogenic effects on normal endothelial cells. Sorafenib and Sunitinib inhibited vascular endothelial cell growth factor receptor2 phosphorylation of prostate cancer endothelial cells, while they differentially modulated Akt phosphorylation as no inhibitory effect of Sorafenib was observed on Akt activation. The combined treatment of Casodex reverted the observed resistance to Sorafenib both on cell viability and on Akt activation, whereas it did not modify the response to Sunitinib. CONCLUSIONS: Our study demonstrates a resistant behavior of endothelial cells isolated from prostate cancer to Sorafenib, but not Sunitinib. Moreover, it shows the benefit of a multi-target therapy combining anti-angiogenic and anti-hormonal drugs to overcome resistance.

TOOKAD(®) Soluble vascular-targeted photodynamic (VTP) therapy: determination of optimal treatment conditions and assessment of effects in patients with localised prostate cancer.

OBJECTIVES: To evaluate the optimal treatment conditions and effects of TOOKAD(®) Soluble vascular-targeted photodynamic (VTP) therapy in patients with localised prostate cancer. To evaluate the safety and quality of life after TOOKAD(®) Soluble VTP treatment in patients with localised prostate cancer. PATIENTS AND METHODS: Men (aged >18 years) diagnosed with localised prostate cancer, who were suitable for active surveillance, were invited to take part in the study. Patients who had received prior or current treatment for their cancer were excluded. There were two parts to the study: in part one, patients were assigned to one of two treatment groups based on the size of their prostates (patients with prostate size <60 mL would receive 4 mg/kg TOOKAD(®) Soluble and patients with prostate size ≥60 mL would receive 6 mg/kg TOOKAD(®) Soluble both activated with 200 J/cm light). In part two, patients were assigned to one of two treatment groups based on predefined criteria and received either 4 or 6 mg/kg TOOKAD(®) Soluble and 200 or 300 J/cm light. VTP was conducted under general anaesthesia using TOOKAD(®) Soluble administered intravenously and activated by light-diffusing fibres within the prostate via the perineum. Follow-up was conducted for 6 months. Magnetic resonance imaging (MRI) carried out at 1 week after VTP and transrectal prostate biopsy at 6 months were the key endpoints. Adverse event (AE) recording and patient-reported outcome measures were collected. RESULTS: In all, 86 patients were enrolled in the study and 85 patients received treatment. Of the 85 treated patients, one patient discontinued (due to withdrawal of consent). At 6 months, 61/83 (74%) patients who underwent prostate biopsy had histopathology that was negative for prostate cancer (95% confidence interval (CI) 62.7-82.6%). Considering patients who received 4 mg/kg TOOKAD(®) Soluble and 200 J/cm light (unilateral), which are considered optimal treatment parameters, 38/46 (83%) patients had histopathology from the biopsies that was negative for prostate cancer at 6 months (95% CI 68.6-92.2%; P < 0.001). The mean percentage of necrosis of the targeted prostate tissue at 7 days after VTP was 78% overall (83 patients) with extraprostatic necrosis reported in 76% (63/83) of patients. Considering patients who received 4 mg/kg TOOKAD(®) Soluble and 200 J/cm light (unilateral), the mean 7-day necrosis percentage was 88% (46 patients) with extraprostatic necrosis reported in 72% (33/46) of patients. All occurrences of extraprostatic necrosis were considered clinically acceptable and none were associated with any clinical sequelae. The mean percentage prostate necrosis at 7 days was statistically significantly higher (P < 0.001) in patients treated with a therapeutic light density index (LDI) of ≥1 than those treated with a LDI of <1. The percentage of patients with negative biopsies at 6 months was also higher in patients treated with a therapeutic LDI of ≥1 than those treated with a LDI of <1 (78.6% and 63.0%, respectively). In all, 87% (75/86) of patients reported at least one treatment-emergent AE during the study. Most AEs were mild or moderate in intensity and considered related to the technical procedures of the study. No treated patients had hypotension or discontinued due to AEs. Eight patients (9.3%) had serious AEs; none resulted in discontinuation from the study. CONCLUSIONS: Biopsy data, post-treatment dynamic contrast-enhancement MRI at 1 week after VTP and analysis of the safety data have shown that 4 mg/kg TOOKAD(®) Soluble and 200 J/cm light are the optimal treatment conditions for the VTP procedure resulting in >80% of patients treated with this regimen having a negative biopsy at 6 months. Overall, the treatment was well tolerated and exhibited early signs of efficacy for minimally invasive focal treatment of localised prostate cancer.

Malignant retroperitoneal fibrosis: MRI characteristics in 50 patients.

We analyzed magnetic resonance imaging (MRI) morphologic patterns of retroperitoneal fibrosis (RF) to identify those able to distinguish malignant RF (mRF) from idiopathic RF (iRF). This retrospective study concerned 50 consecutive patients with MRI-based RF diagnoses, 35 of whom also had histologically proven RF. Previous radiotherapy, abdominal or pelvic surgery or infection during the preceding 6 months, vascular aneurysm (aorta or iliac artery), presence of retroperitoneal multiple nodular masses, or enlarged lymph nodes with a diameter >15 mm constituted exclusion criteria. Patients with mRF differed from those with iRF by age, smoking habits, and follow-up duration but not by clinical manifestations, inflammatory syndrome, or renal insufficiency. MRI-documented mRF extension along the aorta, from above the renal arteries to below the aortic bifurcation, was more frequent than iRF (47% vs. 0%; p = 0.001) but less frequent between the renal arteries and the aortic bifurcation (18% vs. 50%; p = 0.04); mRF extension behind the aorta was wider than iRF (5.0 vs. 2.5 mm; p = 0.03). Neither urinary tract nor vessel involvement differed. Medial ureteral attraction was significantly less frequent in mRF than iRF (24% vs. 83%; p < 0.001), according to univariate and multivariate analyses. An algorithm based on the most discriminant criteria (RF extending from above the renal arteries to below the aortic bifurcation and the absence of medial ureteral attraction) for mRF diagnosis had 82% sensitivity and 83% specificity. When applied to the 15 iRF patients without histologic data, specificity was 73%. This mRF decision tree, consisting of the 2 most discriminant MRI criteria, could be used as a supplementary argument to support RF biopsy.

The accuracy of different biopsy strategies for the detection of clinically important prostate cancer: a computer simulation.

PURPOSE: The true accuracy of different biopsy strategies for detecting clinically significant prostate cancer is unknown, given the positive evaluation bias required for verification by radical prostatectomy. To evaluate how well different biopsy strategies perform at detecting clinically significant prostate cancer we used computer simulation in cystoprostatectomy cases with cancer. MATERIALS AND METHODS: A computer simulation study was performed on prostates acquired at radical cystoprostatectomy. A total of 346 prostates were processed and examined for prostate cancer using 3 mm whole mount slices. The 96 prostates that contained cancer were digitally reconstructed. Biopsy simulations incorporating various degrees of random localization error were performed using the reconstructed 3-dimensional prostate computer model. Each biopsy strategy was simulated 500 times. Two definitions of clinically significant prostate cancer were used to define the reference standard, including definition 1--Gleason score 7 or greater, and/or lesion volume 0.5 ml or greater and definition 2--Gleason score 7 or greater, and/or lesion volume 0.2 ml or greater. RESULTS: A total of 215 prostate cancer foci were present. The ROC AUC to detect and rule out definition 1 prostate cancer was 0.69, 0.75, 0.82 and 0.91 for 12-core transrectal ultrasound biopsy with a random localization error of 15 and 10 mm, 14-core transrectal ultrasound biopsy and template prostate mapping using a 5 mm sampling frame, respectively. CONCLUSIONS: To our knowledge our biopsy simulation study is the first to evaluate the performance of different sampling strategies to detect clinically important prostate cancer in a population that better reflects the demographics of a screened cohort. Compared to other strategies standard transrectal ultrasound biopsy performs poorly for detecting clinically important cancer. Marginal improvement can be achieved using additional cores placed anterior but the performance attained by template prostate mapping is optimal.

Is there a role for α-blockers in ureteral stent related symptoms? A systematic review and meta-analysis.

PURPOSE: We evaluated the efficacy of α-blockers to improve ureteral stent related morbidity and quality of life. MATERIALS AND METHODS: We performed a search of MEDLINE®, Embase™ and The Cochrane Library plus a hand search of conference proceedings from January 2000 to October 2010 to identify randomized, controlled trials comparing treatment for ureteral stent symptoms with α-blockers. Two reviewers independently screened studies and extracted data. Trial methodological quality was assessed by The Cochrane Collaboration quality assessment tool. Placebo randomized, controlled trials with the ureteral stent symptom questionnaire as the outcome were eligible for meta-analysis. Meta-analysis was done using the mean difference to determine the aggregate effect size. RESULTS: A total of 12 randomized, controlled trials including 2 α-blockers in a total of 946 patients were eligible, including 4 (33%) presented only as an abstract at a urological meeting and 4 (33%) eligible for meta-analysis. Meta-analysis using a random effects model showed that α-blockers were associated with a significant decrease in urinary symptoms (MD -6.76, 95% CI -11.52 to -2.00, p=0.005), a significant decrease in pain (MD -3.55, 95% CI -5.51 to -1.60, p=0.0004) and significant improvement in general health (MD -1.90, 95% CI -3.05 to -0.75, p=0.001). However, they were not associated with a benefit in work (MD 2.41, 95% CI -1.62 to 6.44, p=0.24) or sexual matters (MD 0.20, 95% CI -1.06 to 1.45, p=0.33). Eight studies were not included in the meta-analysis, of which 7 showed a significant clinical decrease in urinary symptoms and pain. CONCLUSIONS: Existing evidence from randomized, controlled trials shows that α-blockers are associated with improvement in ureteral stent symptoms and supports their use in routine clinical practice.

[Management of renal atrophy in hypertensive patients: experience in Lille]. / Conduite à tenir devant une atrophie rénale chez le patient hypertendu: l'expérience lilloise.

INTRODUCTION: In the absence of specific treatment, patients with renal vascular disease develop renal atrophy. This population frequently has hypertension refractory to medical treatment. The patients who may respond to revascularization or at the worst to a nephrectomy must be identified to optimize their therapeutic management. METHODS: We conducted an observational retrospective study of hypertensive patients with unilateral renal atrophy (renal height < 9 cm) followed at the Lille University Hospital Center from 1998 to 2006. Hypertension, renal clearance (by scintigraphy with MAG3), and hypersecretion of renin (segmental/selective venous renin samples) were studied. We subsequently classified the patients into 3 groups. Medical treatment was optimized for all. RESULTS: The mean follow-up period was 1.3+/-0.2 years. Eight patients were treated medically (group 1). Endovascular revascularization was used to treat the subjects for which atrophic kidney function accounted for more than 10% of their total renal function and with stenosis of the renal artery (>70%) (group 2, n=19). Those with a small nonfunctional kidney (<10% of total renal function) and hypersecretion of renin (ratio>1.5 in relation to the contralateral kidney) underwent a nephrectomy (group 3, n=8). The reduction in systolic blood pressure (SBP) was 27 mm Hg and diastolic blood pressure (DBP) 14 mm Hg for the overall study population (p < 0.001), without any significant aggravation of renal function. In group 1, the reduction in blood pressure was lower, with medical treatment alone; SBP fell by 13 mm Hg and DBP by 4mm Hg (p=ns) ; this group had the lowest initial blood pressure. In group 2, revascularization made it possible to improve SBP by 26 mm Hg and DBP by 14 mm Hg (p < 0.01) without significant impairment of renal function. Group 3 showed the most spectacular improvement in blood pressure, with SBP dropping by 40 mm Hg and DBP by 19 mm Hg (p=0.016). But it was also in this group that we observed an aggravation in the rate of glomerular filtration with a nonsignificant reduction of 12.8 mL/min, nonetheless superior to that expected according to the preoperative scintigraphy. CONCLUSION: The results of this work underline the importance of multidisciplinary management of patients with small ischemic kidneys. Preselection of patients in unstable clinical situations (refractory hypertension, progressive kidney failure, flash pulmonary edema) by isotopic and endocrinal renal evaluation provides a basis for deciding on treatment. The existence of a renin ratio >1.5 can identify the patients most likely to respond to nephrectomy. The reduction of renal function following nephrectomy must be considered in the discussion about treatment. The functional threshold initially defined at 10% may be lowered to 5%, to limit this postoperative reduction.

Positive surgical margin appears to have negligible impact on survival of renal cell carcinomas treated by nephron-sparing surgery.

BACKGROUND: The occurrence of positive surgical margins (PSMs) after partial nephrectomy (PN) is rare, and little is known about their natural history. OBJECTIVE: To identify predictive factors of cancer recurrence and related death in patients having a PSM following PN. DESIGN, SETTING, AND PARTICIPANTS: Some 111 patients with a PSM were identified from a multicentre retrospective survey and were compared with 664 negative surgical margin (NSM) patients. A second cohort of NSM patients was created by matching NSM to PSM for indication, tumour size, and tumour grade. MEASUREMENTS: PSM and NSM patients were compared using student t tests and chi-square tests on independent samples. A Cox proportional hazards regression model was used to test the independent effects of clinical and pathologic variables on survival. RESULTS AND LIMITATIONS: Mean age at diagnosis was 61+/-12.5 yr. Mean tumour size was 3.5+/-2 cm. Imperative indications accounted for 39% (43 of 111) of the cases. Some 18 patients (16%) underwent a second surgery (partial or total nephrectomy). With a mean follow-up of 37 mo, 11 patients (10%) had recurrences and 12 patients (11%) died, including 6 patients (5.4%) who died of cancer progression. Some 91% (10 of 11) of the patients who had recurrences and 83% of the patients (10 of 12) who died belonged to the group with imperative surgical indications. Rates of recurrence-free survival, of cancer-specific survival, and of overall survival were the same among NSM patients and PSM patients. The multivariable Cox model showed that the two variables that could predict recurrence were the indication (p=0.017) and tumour location (p=0.02). No other variable, including PSM status, had any effect on recurrence. None of the studied parameters had any effect on the rate of cancer-specific survival. CONCLUSIONS: PSM status occurs more frequently in cases in which surgery is imperative and is associated with an increased risk of recurrence, but PSM status does not appear to influence cancer-specific survival. Additional follow-up is needed.

[Bulletin of synthesis 2005. Recommendations for clinical practice. Management of non metastatic prostate cancer]. / Bulletin de synthèse de veille 2005. Recommandations pour la pratique clinique. Prise en charge thérapeutique du cancer de la prostate non métastatique.

This paper is based on the bulletin of synthesis 2005. Management of non metastatic prostate cancer. Recommendations for clinical practice of the French Urologial Association and the National Federation of Anticancer Centers.

[Follow-up of prostate cancer. Guidelines of the Comité de Cancérologie de l'Association Française d'Urologie]. / Suivi du cancer de la prostate.

The follow-up of prostate cancer is especially justified now that effective treatment options are available in the case of recurrence. Conditions of follow-up of patients with prostate cancer vary according to age, comorbidities, tumour stage, prognostic factors at diagnosis and the pervious treatment sequence.