Christopher Morash

Active Surveillance of Small Renal Masses: Progression Patterns of Early Stage Kidney Cancer ☆

BACKGROUND Most early stage kidney cancers are renal cell carcinomas (RCCs), and most are diagnosed incidentally by imaging as small renal masses (SRMs). Indirect evidence suggests that most small RCCs grow slowly and rarely metastasize. OBJECTIVE To determine the progression and growth rates for newly diagnosed SRMs stratified by needle core biopsy pathology. DESIGN, SETTING, AND PARTICIPANTS A multicenter prospective phase 2 clinical trial of active surveillance of 209 SRMs in 178 elderly and/or infirm patients was conducted from 2004 until 2009 with treatment delayed until progression. INTERVENTION Patients underwent serial imaging and needle core biopsies. MEASUREMENTS We measured rates of change in tumor diameter (growth measured by imaging) and progression to ≥ 4 cm, doubling of tumor volume, or metastasis with histology on biopsy. RESULTS AND LIMITATIONS Local progression occurred in 25 patients (12%), plus 2 progressed with metastases (1.1%). Of the 178 subjects with 209 SRMs, 127 with 151 SRMs had>12 mo of follow-up with two or more images, with a mean follow-up of 28 mo. Their tumor diameters increased by an average of 0.13 cm/yr. Needle core biopsy in 101 SRMs demonstrated that the presence of RCC did not significantly change growth rate. Limitations included no central review of imaging and pathology and a short follow-up. CONCLUSIONS This is the first SRM active surveillance study to correlate growth with histology prospectively. In the first 2 yr, the rate of local progression to higher stage is low, and metastases are rare. SRMs appear to grow very slowly, even if biopsy proven to be RCC. Many patients with SRMs can therefore be initially managed conservatively with serial imaging, avoiding the morbidity of surgical or ablative treatment.

Outcomes of Initial Surveillance of Invasive Squamous Cell Carcinoma of the Penis and Negative Nodes

PURPOSE We determined factors predictive of inguinal nodal relapse in patients with stages T1 to 3NOMO squamous cell penile cancer treated initially with surveillance of inguinal nodes. MATERIALS AND METHODS Between 1980 and 1994, in 42 patients with stages T1 to 3NOMO squamous cell penile cancer of 60 with invasive disease seen at our center the inguinal nodes were surveyed after definitive treatment of the primary tumor. Clinical inguinal nodal recurrences were treated with inguinal lymphadenectomy. RESULTS A total of 26 patients (62%) had inguinal nodal recurrences during followup, with 50% occurring within 1.4 years and 75% within 2.8 years of resection of the primary tumor. The only factor predicting nodal relapse was grade of the primary tumor at initial treatment. Patients with grade 1 tumors had a 45% long-term actuarial relapse-free survival rate. All other groups had a 100% actuarial nodal relapse rate. Of the patients 10% had metastatic disease without nodal recurrence. CONCLUSIONS Invasive penile cancer may be associated with inguinal lymph node and hematogenous metastasis. A strong case for prophylactic bilateral inguinal lymphadenectomy can be made in patients with primary tumors other than grade 1, since surveillance of these patients will not spare them eventual lymphadenectomy and may potentially compromise survival by delaying surgery. Patients with grade 1 tumors may be offered either careful surveillance or prophylactic bilateral inguinal lymphadenectomy depending on the clinical circumstances and patient preference.

Radiotherapy and androgen deprivation in combination after local surgery (RADICALS): a new Medical Research Council/National Cancer Institute of Canada phase III trial of adjuvant treatment after radical prostatectomy.

Radiotherapy and androgen deprivation in combination after local surgery (RADICALS): A new Medical Research Council/National Cancer Institute of Canada phase III trial of adjuvant treatment after radical prostatectomy Chris Parker, Matthew R. Sydes 1 , Charles Catton 2 , Howard Kynaston 3 , John Logue , Claire Murphy 1 , Rachel C. Morgan 1 , Kilian Mellon 5 , Chris Morash 6 , Wendy Parulekar 7 , Mahesh K.B. Parmar 1 , Heather Payne 8 , Colleen Savage 7 , Jim Stansfeld 9 and Noel W. Clarke 10 (The RADICALS Trial Management Group) Academic Unit of Radiotherapy & Oncology, Institute of Cancer Research and the Royal, Marsden NHS Foundation Trust, Sutton, Surrey, 1 Medical Research Council (MRC) Clinical Trials Unit, London, UK, 2 Princess Margaret Hospital, Toronto, Ontario, Canada, 3 Department of Urology, University Hospital of Wales, Heath Park, Cardiff, 4 Christie Hospital NHS Trust, Manchester, UK, 5 Urology Section, University of Leicester, UK, 6 University of Ottawa, The Ottawa Hospital General Campus, Ottawa, 7 National Cancer Institute of Canada (NCIC) Clinical Trials Group, Kingston, Ontario, Canada, 8 Department of Oncology, University College Hospital, London, UK, 9 Hon. Treasurer, PCaSO Prostate Cancer Network, Emsworth, Hants, UK, 10 Salford Royal Hospitals NHS Trust, Salford, UK

Pathologic findings at the time of nephrectomy for renal mass

AbstractBackground: Ultrasound (US) and computed tomography (CT) have improved the diagnosis of solid renal masses. Nevertheless, some patients still undergo exploration for a presumptive diagnosis of renal cell carcinoma (RCC) and are found to have other pathology. We report a contemporary series of non-RCC renal masses (both incidental and symptomatic) among nephrectomies performed for suspected RCC. Materials and Methods: All nephrectomies performed by the Urology Service at the Memorial Sloan-Kettering Cancer Center from July of 1989 through July of 1996 for a parenchymal renal mass were reviewed, and patients without a final diagnosis of RCC were identified. Cases were excluded if RCC was not suspected preoperatively. Presentation, preoperative radiographic evaluation, type of operation, and pathologic features were assessed. Results: Of the 636 nephrectomies performed, 108 patients (16.9%) had a diagnosis other than RCC. Conclusions: Of patients undergoing nephrectomy for renal masses, 16.9% have other pathologic diagnoses. Sixty-six percent of these non-RCC masses are discovered incidentally, and the majority are treated with radical nephrectomy. Preoperative radiographic evaluation reflects both clinical presentation, with IVP used to evaluate symptomatic tumors, and diagnostic uncertainty, with multiple modalities used to evaluate cystic lesions. This information has important implications for preoperative counseling and surgical planning.

Active surveillance for the management of localized prostate cancer: Guideline recommendations

INTRODUCTION The objective is to provide guidance on the role of active surveillance (AS) as a management strategy for low-risk prostate cancer patients and to ensure that AS is offered to appropriate patients assessed by a standardized protocol. Prostate cancer is often a slowly progressive or sometimes non-progressive indolent disease diagnosed at an early stage with localized tumours that are unlikely to cause morbidity or death. Standard active treatments for prostate cancer include radiotherapy (RT) or radical prostatectomy (RP), but the harms from over diagnosis and overtreatment are of a significant concern. AS is increasingly being considered as a management strategy to avoid or delay the potential harms caused by unnecessary radical treatment. METHODS A literature search of MEDLINE, EMBASE, the Cochrane library, guideline databases and relevant meeting proceedings was performed and a systematic review of identified evidence was synthesized to make recommendations relating to the role of AS in the management of localized prostate cancer. RESULTS No exiting guidelines or reviews were suitable for use in the synthesis of evidence for the recommendations, but 59 reports of primary studies were identified. Due to studies being either non-comparative or heterogeneous, pooled meta-analyses were not conducted. CONCLUSION The working group concluded that for patients with low-risk (Gleason score ≤6) localized prostate cancer, AS is the preferred disease management strategy. Active treatment (RP or RT) is appropriate for patients with intermediate-risk (Gleason score 7) localized prostate cancer. For select patients with low-volume Gleason 3+4=7 localized prostate cancer, AS can be considered.

Preservation of Renal Function Following Partial or Radical Nephrectomy Using 24-Hour Creatinine Clearance

OBJECTIVE To compare the effect on renal function of partial and radical nephrectomy using creatinine clearance measurements from 24-hr urine collection. METHODS All patients with a solid enhancing renal mass suspicious for renal cell carcinoma, a normal contralateral kidney, and not dialysis dependent were enrolled in this prospective cohort study. Patients were treated with partial or radical nephrectomy by one urologist. Creatinine clearance (CrCl) measurements were prospectively obtained by 24-hr urine collection preoperatively, and at 3, 6, and 12 mo postoperatively. Mean change in creatinine clearance from baseline was compared at 3, 6, and 12 mo. Serum creatinine and Cockcroft-Gault calculations were also performed for comparison. Mixed model analysis incorporating patient and tumor characteristics and the procedure type was performed in SAS Version 9.1. RESULTS Sixty-three consecutive patients were enrolled in this study. The partial nephrectomy (n=26) and radical nephrectomy (n=37) groups were similar with respect to age, sex, presence of hypertension, vascular disease, diabetes mellitus, and angiotensin converting enzyme inhibitor or receptor blocker use. The postoperative change in creatinine clearance was significantly less (p-value < 0.0001) in the partial nephrectomy group (-0.09mL/s, -6.1%) compared to the radical nephrectomy group (-0.56mL/s, -31.6%). Linear regression analysis showed intervention type (partial vs. radical nephrectomy) was the most significant predictor of change in creatinine clearance (p-value < 0.0001). CONCLUSIONS There is significantly less deterioration in the overall renal function of patients who are treated with partial nephrectomy compared to radical nephrectomy. This highlights the importance of performing nephron-sparing surgery on appropriate patients.

Peri-operative morbidity associated with radical cystectomy in a multicenter database of community and academic hospitals.

Objective To characterize the frequency and timing of complications following radical cystectomy in a cohort of patients treated at community and academic hospitals. Patients and Methods Radical cystectomy patients captured from NSQIP hospitals from January 1 2006 to December 31 2012 were included. Baseline information and complications were abstracted by study surgical clinical reviewers through a validated process of medical record review and direct patient contact. We determined the incidence and timing of each complication and calculated their associations with patient and operative characteristics. Results 2303 radical cystectomy patients met inclusion criteria. 1115 (48%) patients were over 70 years old and 1819 (79%) were male. Median hospital stay was 8 days (IQR 7–13 days). 1273 (55.3%) patients experienced at least 1 post-operative complication of which 191 (15.6%) occurred after hospital discharge. The most common complication was blood transfusion (n = 875; 38.0%), followed by infectious complications with 218 (9.5%) urinary tract infections, 193 (8.4%) surgical site infections, and 223 (9.7%) sepsis events. 73 (3.2%) patients had fascial dehiscence, 82 (4.0%) developed a deep vein thrombosis, and 67 (2.9%) died. Factors independently associated with the occurrence of any post-operative complication included: age, female gender, ASA class, pre-operative sepsis, COPD, low serum albumin concentration, pre-operative radiotherapy, pre-operative transfusion >4 units, and operative time >6 hours (all p<0.05). Conclusion Complications remain common following radical cystectomy and a considerable proportion occur after discharge from hospital. This study identifies risk factors for complications and quality improvement needs.

Nerve Growth Factor Modulation of the Cavernous Nerve Response to Injury

INTRODUCTION Surgical therapies for prostate cancer and other pelvic malignancies often result in neuronal damage and debilitating loss of sexual function due to cavernous nerve (CN) trauma. Advances in the neurobiology of growth factors have heightened clinical interest in the development of protective and regenerative neuromodulatory strategies targeting CN recovery following injury. AIM The aim of this review was to offer an examination of current and future nerve growth factor (NGF) modulation of the CN response to injury with a focus on brain-derived nerve growth factor (BDNF), growth differentiation factor-5 (GDF-5), and neurturin (NTN). METHODS Information for this presentation was derived from a current literature search using the National Library of Medicine PubMed Services producing publications relevant to this topic. Search terms included neuroprotection, nerve regeneration, NGFs, neurotrophic factors, BDNF, GDF-5, NTN, and CNs. MAIN OUTCOME MEASURES Basic science studies satisfying the search inclusion criteria were reviewed. RESULTS In this session, BDNF, atypical growth factors GDF-5 and NTN, and their potential influence upon CN recovery after injury are reviewed, as are the molecular pathways by which their influence is exerted. CONCLUSIONS Compromised CN function is a significant cause of erectile dysfunction development following prostatectomy and serves as the primary target for potential neuroprotective or regenerative strategies utilizing NGFs such as BDNF, GDF-5, and NTN, and/or targeted novel therapeutics modulating signaling pathways.

Postoperative Radiotherapy for Prostate Cancer: A Comparison of Four Consensus Guidelines and Dosimetric Evaluation of 3D-CRT Versus Tomotherapy IMRT

PURPOSE Despite the benefits of adjuvant radiotherapy after radical prostatectomy, approximately one-half of patients relapse. Four consensus guidelines have been published (European Organization for Research and Treatment of Cancer, Faculty of Radiation Oncology Genito-Urinary Group, Princess Margaret Hospital, Radiation Therapy Oncology Group) with the aim of standardizing the clinical target volume (CTV) delineation and improve outcomes. To date, no attempt has been made to compare these guidelines in terms of treatment volumes or organ at risk (OAR) irradiation. The extent to which the guideline-derived plans meet the dosimetric constraints of present trials or of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) trial is also unknown. Our study also explored the dosimetric benefits of intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS A total of 20 patients treated with postoperative RT were included. The three-dimensional conformal radiotherapy (3D-CRT) plans were applied to cover the guideline-generated planning target volumes (66 Gy in 33 fractions). Dose-volume histograms (DVHs) were analyzed for CTV/planning target volume coverage and to evaluate OAR irradiation. The OAR DVHs were compared with the constraints proposed in the QUANTEC and Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trials. 3D-CRT plans were compared with the tomotherapy plans for the Radiation Therapy Oncology Group planning target volume to evaluate the advantages of IMRT. RESULTS The CTV differed significantly between guidelines (p < 0.001). The European Organization for Research and Treatment of Cancer-CTVs were significantly smaller than the other CTVs (p < 0.001). Differences in prostate bed coverage superiorly accounted for the major volumetric differences between the guidelines. Using 3D-CRT, the DVHs rarely met the QUANTEC or RADICALS rectal constraints, independent of the guideline used. The RADICALS bladder constraints were met most often by the European Organization for Research and Treatment of Cancer consensus guideline (14 of 20). The tomotherapy IMRT plans resulted in significant OAR sparing compared with the 3D-CRT plans; however, the RADICALS and QUANTEC criteria were still missed in a large percentage of cases. CONCLUSION Treatment volumes using the current consensus guidelines differ significantly. For the four CTV guidelines, the rectal and bladder DVH constraints proposed in the QUANTEC and RADICALS trials are rarely met with 3D-CRT. IMRT results in significant OAR sparing; however, the RADICALS dose constraints are still missed for a large percentage of cases. The rectal and bladder constraints of RADICALS should be modified to avoid a reduction in the CTVs.

The Prognostic Significance of Capsular Incision Into Tumor During Radical Prostatectomy

BACKGROUND The prognostic significance of capsular incision (CapI) into tumor during radical prostatectomy (RP) with otherwise organ-confined disease remains uncertain. OBJECTIVE To evaluate the impact of CapI into tumor on oncologic outcome. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of 8110 consecutive patients with prostate cancer treated at Ottawa Hospital and at Memorial Sloan-Kettering Cancer Center, both tertiary academic centers, between 1985 and 2008. INTERVENTION All patients underwent an open, laparoscopic or robotic RP. MEASUREMENTS Patients were divided into four pathologic categories: group 1 (CapI group), positive surgical margins (PSMs) without extraprostatic extension (EPE); group 2, negative surgical margins (NSMs) without EPE; group 3, NSM with EPE; group 4, PSMs with EPE. Estimates of recurrence-free survival were generated with the Kaplan-Meier method. Recurrence was defined as a prostate-specific antigen (PSA) >0.2 ng/ml and rising. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for recurrence controlling for pretreatment PSA, RP date, RP Gleason sum, seminal vesicle invasion, and lymph node involvement. Pathologic categories were defined in the model by including the variables EPE and surgical margins (SMs) as well as their interaction. RESULTS AND LIMITATIONS Median follow-up was 37.3 mo. The 5-yr recurrence-free probability after RP for the CapI group was 77% (95% confidence interval [CI], 72-83). This was not only inferior to patients with NSMs and no EPE (log rank p<0.0001) but also to those with NSMs and EPE (log rank p=0.0002). In multivariate analysis the interaction between EPE and SM was not significant (p=0.26). In the adjusted model excluding the interaction term, patients with EPE had an increased risk for recurrence (HR: 1.80; 95% CI, 1.49-2.17; p<0.0001) as did those with positive margins (HR: 1.81; 95% CI, 1.51-2.15; p<0.0001). This was a retrospective study. CONCLUSIONS CapI into tumor has a significant impact on patient outcome following RP. Patients, who otherwise would have organ-confined disease, will now have a higher probability of recurrence than those with completely resected extraprostatic disease.