Genitourinary Cancers

Genitourinary Cancers
 

• CR Pound, AW Partin, MA Eisenberger, et al (Johns Hopkins Med Institutions, Baltimore, Md; Merck Research Labs, Blue Bell, Pa)
  Natural History of Progression After PSA Elevation Following Radical Prostatectomy
  JAMA 281: 1591-1597, 1999.
    
  The natural history of prostate cancer is linked with PSA for diagnosis, prognosis and therapeutic decisions. Patients who have undergone a radical prostatectomy are followed up by serial PSA tests. 
    
  Many patients whose serum PSA increases after radical prostatectomy may remain free of metastases for a prolonged period.
     

• Rithcies AWS, for the Medical Research Council Renal Cancer Collaborators [MRC Cancer Trials Office, Cambridge, England]
  Interferon-alpha and Survival in Metastatic Renal Carcinoma : Early Results of a Randomised Controlled Trial
  Lancer 353: 14-17, 1999
        
  The modalities for therapy of metastatic renal disease are interferon – alpha and medroxyprogesterone acetate [MPA].
    
  This randomized study of patients with metastatic renal disease received interferon or MPA and were monitored upto death. Primary end point was overall survival. Patients treated with interferon had improved 1 year and median survival compared with patients, who received MPA although side effects were more in the interferon arm.
     

• Negrier S, for the Groupe of Francias D’ Immunotherapie [Centre Leon Berard, Lyons, France; Institut Gustave Roussy, Villejuif, France; Centre Rene Gauducheau, Nantes, France; et al]
  Recombinant Human Interleukin-2, Recombinant Human Interferon Alfa-2a, or Both in Metastic Renal – Cell Carcinoma
  N Engl J Med 338:1272-1278, 1998
    
  This study compared the response, event free and overall survival of patients with metastatic renal – cell carcinoma who received IL-2 as 5-day continuous infusion, interferon 18 million units administrated 3 times a week. on both where as patients with metastatic renal cancer receiving both had significantly higher rates of response and event free survival, overall survival was similar to that of either cytokine given alone.
      

• Tourani J-M, for the Subcutaneous Administration Propeukin Program Cooperative Group [Hospital Laennec, France; Hopital de la Pitie Salpetriere, France; Hopital Necker, France; et al]
  Outpatient Treatment with Subcutaneous Interleukin-2 and Interferon Alfa Administration in Combination with Fluorouacil in Patients with Metastatic Renal Cell Carcinoma : Results of a Sequential Nonrandomized Phase II Study
  J Clin Oncol 16: 2505-2513, 1998
    
  This study evaluates the clinical response and toxicity of patients with metastatic renal carcinoma receiving subcutaneous IL-2, and interferon alfa with 5-fluorouracil.
    
  The 3-drug combination was administered to 62 patients. This combination had a response of 19% and did not improve the survival but resulted in significant toxicity.
     

• Hall MC, Womack JS, Roehrborn CG, et al [Univ of Texas, Dallas]
  Advanced Transitional Cell Carcinoma of the Upper Urinary Tract : Patterns of Failure, Survival and Impact of Postoperative Adjuvant Radiotherapy
  J Urol 160: 703-706, 1998
    
  Transitional cell carcinoma of the upper urinary tract underwent surgery with curative intent. The risk of disease relapse and disease related death was high. The major clinical problem was distant metastatic and postoperative adjuvant radiotherapy did not have any survival benefit.
    
  The editor comments that the dose of radiation i.e. only 4000 rad. used in, this study is less as this dose is not sufficient to control transitional cell carcinoma, even microscopically.
        

• Herr HW, Bajorin DF, Scher HI [Mem Sloan-Kettering Cancer Ctr, New York; Cornell Univ, New York]
  Neoadjuvant Chemotherapy and Bladder-Sparing Surgery for Invasive Bladder Cancer : Ten-Year Outcome
  J Clin Oncol 16: 1298-1301, 1998
    
  Radical cystecomy is standard treatment for invasive bladder cancer.
    
  This study of 111 patients surgical candidates with bladder cancer underwent neoadjuvant chemotherapy with methotrexate, vinblastine, adriamycin & cisplatinum, [MVAC] 54 % achieved a complete clinical response. Bladder sparing procedures such as transurethral resection alone or partial cystectomy was possible in majority of patients. To conclude bladder sparing surgery permits bladder preservation for upto 10 years in most patients with invasive bladder tumors who attain TO status after neoadjuvant MVAC chemotherapy. Most but not all, relapsing patients can be salvaged with cystectomy.
     

• Fizazi K, Culine S, Droz J-P, et al [ Institut Gustave-Roussy, Villejuif, France]
  Primary Mediastinal Nonseminomatous Germ Cell Tumors : Results of Modern Therapy Including Cisplatin-based Chemotherapy
  J Clin Oncol 16: 725-732, 1998
     
  Primary mediastinal nonseminomatous germ cell tumours [NSGCT] are uncommon neoplasms clinically and biologically distinct from other germ cell tumors [GCT].
    
  In this study 38 patients with mediastinal NSGCT were treated with cisplatin based chemotherapy as part of their primary treatment with chemotherapy and surgery. Complete response was obtained in 66% at a median follow of 9 month. 34.5% of the patients continued to be free of disease. All patients not achieving CR died of their disease. To conclude 40% of patients with primary mediastinal NSGCT can be expected to survive in the long term with cisplatin based chemotherapy followed by surgical resection of residual masses.
     
  The editor comments that patients with mediastinal NSGCT are associated with Klinefelter’s syndrome, non-germ-cell malignant disease such as rhabdomyosarcoma, adenocarcinoma, neuroectodemal tumors and hematologic malignancies particularly AML-M7.
       

• Henricks WH, England BG, Giacherio DA, et al [ Univ of Michigan, An Arbor ]
  Serum Percent – Free PSA Does not Predict Extraprostatic Spread of Prostate Cancer
  Am J Clin Pathol 109: 533-539, 1998
    
  Prostate-specific antigen [PSA] which is not complexed to other proteins is called free PSA. This component of PSA is more useful than total PSA for differentiating between benign and malignant conditions of prostate. Percent free PSA values in frozen serum samples of 130 men having radical prostatectomy for clinically localized prostate cancer were analyzed across pathologic stage. Multiple freeze-thaw cycles do not significantly alter free PSA and was not useful for identifying candidates for radical prostatectomy.
        

• Debras B, Guillonneau B, Bougaran J, et al [ universite Pierre et Marie Curie, Paris ]
  Prognostic Significance of Seminal Vesicle Invasion on the Radical Prostatectomy Specimen : Rationale for Seminal Vesicle Biopsies
  Eur Urol 33: 271-277, 1998
     
  Seminal vesicle invasion [SVI] is found in 7-30% of patients undergoing radical prostatectomy.
    
  This study of 52 patients who underwent radical prostatectomy and had SVI were evaluated. Those who had limited SVI had a significantly better rate of progresson free survival (using PSA as parameter) than those with extension involvement all the way to the  free part of seminal vesicle.
     

• Valicenti RK, Gomella LG, Ismail M, et al [ Thomas Jefferson Univ, Philadelphia ]
  Pathologic Seminal Vesicle Invasion After Radical Prostatectomy for Patients with Prostate Carcinoma : Effect of Early Adjuvant Radiation Therapy on Biochemical Control
  Cancer 82: 1909-1914, 1998
     
  The role of adjuvant radiotherapy in patients following radical prostatectomy when seminal vesicle invasion [SVI] is involved is unknown. This study of 53 patients with documented prostate cancer involving the seminal vesicle revealed that those patients who had an elevated PSA following radical prostatectomy and received salvage RT had a poor 3 year rate of freedom of biochemical failure whereas those with normal PSA irradiation was useful.
       

• Eisenberger MA, Blumenstein BA, Crawford ED, et al [ Johns Hopkins Hosp, Baltimore Md, Southwest Oncology Group Statistical Ctr, Seattle; Univ of Colorado, Denver; et al ]
  Bilateral Orchidectomy With or Without Flutamide for Metastatic Prostate Cancer
  N Engl J Med 339: 1036-1042, 1998
     
  Metastatic prostate cancer is not a curative disease, however androgen blockade suppresses tumor growth initially as the diseases progresses to a hormone insensitive phase. The study of patients with metastatic adenocarcinoma of the prostate following bilateral orchidectomy were randomise to receive flutamide [n=698] or placebo [n=687]. Although the flutamide group had significantly higher percentage of PSA response. The survival rate were similar in both groups. The editor comments that this study has finally put to rest the concept of combined androgen blockade [i.e. LHRH agonist treatment antiandrogen] once very popularly practiced in patients with metastatic prostate cancer.
     

• Eastham JA, Kattan MW, Groshen S, et al [ Baylor College of Medicine, Houston; St Luke’s Episcopal Hosp, Houston; Univ of Southern California, los Angeles ]
  Fifteen-Year Survival and Recurrence Rates after Radiotherapy for Localized Prostate Cancer
  J Clin Oncol 15: 3214-3222, 1997
    
  The optimum therapy for localized prostate cancer is not clear.
    
  This study of 136 patients with clinically localized prostate cancer treated with interstital and external beam irradiation following surgery with pelvic lymphadenectomy were analyzed. Overall 44% of patients had no recurrence in 15 years or more after treatment. Patients with stage A2 and B tumors and negative nodes have a favorable cancer-specific mortality at 15 years or longer after radiation therapy. Eastimated probability of death from prostate cancer at 15 years was about 33% and from all cause 72%. The presence of nodal metastases was the most powerful prognostic factor.
     

• Dawson NA, Figg WD, Cooper MR, et al [ Natl Cancer Inst, Bethesda, Md ]
  Phase II Trial of Suramin, Leuprolide, and Flutamide in Previously Untreated Metastatic Prostate Cancer
  J Clin Oncol 15: 1470-1477, 1997
    
  This study of 50 patients with metastatic carcinoma prostate were treated with flutamide leuprolide and suramin along with hydrocortisone as replacement for suramin induced adrenal insufficiency.
     
  The overall response rate was 69%. Partial remission ranging in duration from 5 months to more than 61 months, occured in 30 [60%] patients, 10 of whom had not progressed at follow-up ranging from 10 to 61 months 36[72%] have progressed. Progressive disease develops in nearly all patients with metastatic prostate cancer however, these three drugs therapy had a high response rate and prolonged survival and a decline in prostate specific antigen to less than 0.5% ng/ml was associated with 92% -2-year survival.
     

• Satariano WA, Regland KE, Van Den Eeden SK [ Univ of California, Berkeley; Kaiser Permanente, Oakland, Calif
  Cause of Death in Men Diagnosed with Prostate Carcinoma
  Cancer 83: 1180-1188, 1998
    
  Prostate cancer is the most frequent cancer of male in United States. It being the disease of the elderly cause of the death could be due to other comorbid conditions.
     
  Patients were most likely to die of prostate cancer if they were black, 65 years or older, advanced disease stage & recipients of hormonal therapy. Approximately 50% of males diagnosed with prostate cancer died of some other cause, particularly older males and those with cardiovascular comorbid condition. Black males were most likely to die due to prostate cancer.
     

• Van der Kwast TH, Labrie F, Tetu B [Erasmus Univ Rotterdam, The Netherlands; Laval Univ Med Ctr, Quebec, Canada]
  Persistence of High-Grade Prostatic Intra-Epithelial Neoplasia Under Combined Androgen Blockade Therapy
  Hum Pathol 30 :1503-1507, 1999
    
  This study has documented persistent prostatic [PIN] intraepithelial neoplasia after androgen blockade and the editor comment if indeed PIN is a precursor for adenocarcinoma of prostate newer nonhormonal ways of treatment may be required to prevent cancer.
     

• Balaji KC, Rbbani F, Tsai H, et al [ Mem Sloan-Kettering Cancer Ctr, New York] 
  Effect of Neoadjuvant Hormonal Therapy on Prostatic Intraepithelial Neoplasia and its Prognostic Significance
  J Urol 162: 753-757, 1999
    
  This study tried to focus on interrelation between PIN, prostate specific antigen [PSA] and its impact on neoadjuvant hormonal therapy and recurrence of PSA was not significantly influenced by either PIN or hormonal therapy at follow-up. However, hormonal therapy may decrease the incidence of PIN in these patients.
       

• Aqua DB, Cordon-Cardo C, Fox W, et al [ Mem Sloan-Kettering Cancer Ctr, New York]
  Prostate Cancer Cell Cycle Regulators : Response to Androgen Withdrawal and Development of Androgen Independence
  J Natl Cancer Inst 91: 1869-1876, 1999
     
  Androgen withdrawal is a standard modality for advanced prostate cancer. This study done on tumor in nude athymic mice were sampled after androgen withdrawal and when androgen independence had developed, tumor regression resulted from cell cycle arrest and androgen independence was associated with a release from the cell cycle. 
        

• Stanford JL, Feng Z, Hamliton AS, et al [ Univ of Washington, Seattle; Univ of Southern California, Los Angeles; Univ of New Mexico, Albuquerque; et al]
  Urinary and Sexual Function After Radical Prostatectomy for Clinically Localized Prostate Cancer: The Prostate Cancer Outcomes Study
  JAMA 283: 354-360, 2000
    
  This study on 1291 white, black and hispanic males who had undergone radical prostatectomy for localized carcinoma prostate were evaluated for urinary and sexual function at a follow-up of 18 months or more, 8.4% of men were incontinent and 59.9% were impotent. This was higher if non-nerve-sparing surgery was performed. The urinary incontinence was higher in elderly patients [ i.e. 75-79 years]. This data would be useful for making treatment decisions.
       

• Messing EM, Manola J, Sarosdy M, et al [Univ of Rochester, NY; Dana-Farber Cancer Inst, Boston; Univ of Texas, San Antonio; et al]
  Immediate Hormonal Therapy Compared with Observation After Radical Prostatectomy and Pelvic Lymphadenectomy in Men With Node-Positive Prostate Cancer
  N Engl J Med 341: 1781-1788, 1999
     
  This study of 100 men with clinically localized prostate cancer were randomized to immediate or delayed antiandrogen [either goserelin 3.6 mg subcutaneous every 28 days or a bilateral orchiectomy]. i.e. at the time of disease progression. All these 100 men had undergone radical prostatectomy and pelvic lymph node dissection for nodal metastasis. Patient with node positive prostate cancer benefited from immediate anti androgen therapy and pelvic lymphadenectomy. The risk of recurrence was reduced and survival rate also improved in the early treatment arm.
         

• International Collaboration of Trialists on Behalf of the Medical Research Council Advanced Bladder Cancer Working Party, EROTC Genito-Urinary Group, Australian Bladder Cancer Study Group, et al [Clinical Trials Unit, London; et al]
  Neoadjuvant Cisplatin, Methotrexate, and Vinblastine Chemotherapy for Muscle-Invasive Bladder Cancer : A Randomised Controlled Trial
  Lancet 354: 533-540, 1999
    
  This study of patients with transitional cell carcinoma who underwent curative cystectomy or full-dose external beam radiotherapy were randomized to 3 cycles of neoadjuvant chemotherapy [ cisplatin, methotrexate, vinblastine and folinic acid] i.e. prior to the local therapy. n=491 and 485 patients who did not receive chemotherapy. For chemotherapy group median survival was 44 months, and for no-chemotherapy group – 37.5 months. In 32.5% of cystectomy samples there was no evidence of tumor after neoadjuvant chemotherapy. Although this higher pathologic response in cystectomy specimen following chemotherapy did not translate in improved survival rate. The editor comments an study with neoadjuvant M-VAC would be worth as this is the only regimens proven to have survival advantage in patients with advanced transitional disease. 
         

• Shipley WU, Thames HD, Sandler HM, et al [ Harvard Med School, Boston; Univ of Texas, Houston; Univ of Michigan, Ann Arbor; et al]
  Radiation Therapy for clinically Localized Prostate Cancer: A Multi-Institutional Pooled Analysis
  JAMA 281: 1598-1604, 1999
    
  This study of 1765 men with prostate cancer [ T1b, T1c, and T2 ] received external beam radiotherapy. The results revealed long term survival of freedom from biochemical relapse following external beam therapy. They showed lower PSAs are better than higher PSAs prognostically and that Gleason score of 6 and under are better than 7 and above prognostically. 
         

• Zagars GK, Pollack A, Smith LG [ Univof Texas, Houston]
  Conventional External-Beam Radiation Therapy Alone or With Androgen Ablation for Clinical Stage III [T3, NX/NO,MO] Adenocarcinoma of the Prostate
  Int J Radiat Oncol Biol Phys 44: 809-819, 1999
   
  This study of 344 patients T3, NO/NX, MO adenocarcinoma of prostate undergoing conventional irradiation alone and or with androgen ablation were analyzed for relapses on increasing PSA. Conventional irradiation alone is minimally curative in patients with stage III adenocarcinoma of prostate and doses of less than 68 Gy were ineffective. Men with lower PSA [less than o] would benefit from conventional irradiation upto 70-Gy and other benefit from combined approach i.e. irradiation and androgen ablation or high dose conformal irradiation. . 
    
  The editor comments the question remains whether higher doses of conformal technique will have significant improvement obviating the need for androgen ablation.
         

• Lara PD, Perez S, Rey A, et al [Hosp Neustra Senora del Pino, Las Palmas de Gran Canaria, Spain]
  Apoptosis in Carcinoma of the Bladder : Relation With Radiation Treatment Results 
  Int J Radiat Oncol Biol Phys 43: 1015-1019, 1999
    
  This study of 55 patients with invasive bladder carcinoma were treated with radiotherapy. Petreatment apoptotic indices were associated with tumor stage, mitotic index, ki-67 proliferation index, local control and survival rates were better in patients with tumors with low pretreatment apoptotic indices than in those with highly apoptotic tumors. The editor comments that biological tumor characteristics may enable effective patient selection for different therapeutic modalities.
       

• Bloomfield DJ, Krahn MD, Neogi T, et al [Univ of Toronto; McMaster Univ; Tom Baker Cancer Ctr, Calgary, Canada; et al]
  Economic Evaluation of Chemotherapy With Mitoxantrone Plus Prednisone for Symptomatic Hormone-Resistant Prostate Cancer: Based on a Canadian Randomized Trial With Palliative End Points
  J Clin Oncol 16: 2272-2279, 1998
      
  Hormone refractory prostate cancer [HRPC] is inevitably fatal. The Cost analysis of 161 patients of HRPC who were randomized to mitoxantrone + prednisone [M+P] or prednisone alone although survival did not differ, M+P had better palliation. In a cost utility M+P was preferred strategy.
         

• Sabah Sallah, and Gregory A. Gagnon (Division of Hematology/Oncology, Department of Medicine, University of Tennessee, Memphis, Memphis, Tennessee; Department of Pathology and Laboratory Medicine, East Carolina University, School of Medicine, Greenville, North Carolina)
  Reversion of Primary Hyperfibrinogenolysis in Patients with Hormone-Refractory Prostate Cancer Using Docetaxel 
  Cancer Investigation 2000 Vol. 18 (3) Pg. 191-196
       
  The role of proteases such as urokinase plasminogen activator (u-PA) in proteolytic degradation of the matrix proteins increases its metastatic potential. 
       
  This is documented in breast and prostate cancer.
      
  This study of eight patients with hormone refractory prostate cancer and hyperfibrinogenolysis received docetaxel along with replacement of depleted blood components and heparinization as appropriate. Four patients had resolution of fibrinogenolysis after one cycle of docetaxel. Four patients had a PSA response (i.e. 50% reduction). The response is believed to be due to antitumor effect.
        

• Margaret Choy, and Shahin Rafii (Laboratory of Vascular Hematology, Division of Hematology/Medical Oncology, Weill Medical College of Cornell University, New York, New York)
  Role of Angiogenesis in the Progression and Treatment of Prostate Cancer 
  Cancer Investigation 2001 Vol. 19 (2) Pg. 181-191
        
  Tumor growth requires active neovascularization a process referred to as angiogenesis. In turn tumor cells promote neo-angeogenesis by releasing endothelial growth factors which support endothelial cell survival, migration and proliferation. Recent data supports growth and metastasis of prostate cancer angiogenesis dependent. 
       
  Endothelial mitogens such as vascular endothelial growth factors (VEGF) and fibroblast growth factor (FGF) in conjunction with angiopoietins and other unknown factors regulate proliferation and remodeling of endothelial cells during neo-angiogenesis. 
       
  The normal and malignant prostate epithelial cells express VEGF and patients with metastatic prostate cancer have elevated VEGF serum level. Recent studies have revealed VEGF expression is enhanced by androgen. 
       
  The anti-angiogenic strategies devised for prospective treatment of solid tumors include neutralising blocking agents against pro-angiogenic factors such as VEGF and the receptors. Extracellular matrix degrading enzymes play an important role in angiogenesis. Two major groups of enzymes included a metalloproteinase MMP and urokinase families. 
         
  Several agents undergoing trials have MMP inhibitor properties such as AG 3340. The other ways of anti-angiogenic therapy include modulating the endothelial-targeted growth factor / cytokine expression and other anti-angiogenic agents which have yet unknown mechanism of action such as angiostatin endostatin TNP-470 and prostate specific antigen. 
       
  To conclude the next decade would lead us to clinical use of anti-angiogenic agents in treatment of prostate cancer apart from hormone ablations, chemotherapy and radiation. 
       

• David J. Vaughn and S. Bruce Malkowicz (Division of Hematology/Oncology, Department of Medicine, and Department of Urology, University of Pennsylvania School of Medicine and the University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania) 
  Recent Advances in Bladder Cancer Chemotherapy 
  Cancer Investigation 2001 Vol. 19 (1) Pg. 77-85
         
  Transitional cell carcinoma of bladder is chemotherapy-sensitive neoplasm. Approximately 50% of patients with muscle-invasive bladder cancer will develop metastatic disease.
         
  Cisplatinum based regimen such as MVAC have become standard for patients with metastatic urothelial cancer. Predictions of poor outcome included nontransitional histology, poor performance status and/or bone visceral metastasis. The toxicity of MVAC such as mucositis, myelosuppression is well documented.
          
  Newer agent with significant activity include the taxanes, paclitaxel, docetaxel, gemcitabine, ifosfamide and methotrexate analogues trimetrexate and piritrexin.
          
  Paclitaxel as a single agent has significant activity and hence in combination with carboplatinum revealed response in the range of 14% to 65% depending on various tumor related and dose related factors. 
          
  Other doublets and triplets regimens such as paclitaxel+cisplat, docetaxel+cisplat and paclitaxel/ifosfamide/cisplat respectively when used in advanced urothelial malignancy had shown response. Gemcitabine+cisplatinum had responses above 50% with good tolerability.
         
  In one study using triplet paclitaxel/gemcitabine/platinum, the response rates were above 70%. However, this combination requires further studies. The benefit of adjuvant chemotherapy in bladder cancer has not been documented in sufficiently powered randomized study.
        
  However, in study using clyclophosphamide/doxorubicin/cisplat for pT3-T4 and/or node positive patients did demonstrate a delay in time to progression in favor of adjuvant chemotherapy. Outside clinical trial most investigators would recommend MVAC adjuvant chemotherapy for high risk resected disease (extravesical extension or micro metastasis to regional nodes).
          
  The neoadjuvant chemotherapy has not had an impact on survival. The prognosis depends on biological factors, those with altered p53 and p21 expression had poor outlook.
          

• Mark G. Swanson, Daniel B. Vigneron, et al (Magnetic Resonance Science Center, University of California, San Francisco, San Francisco, California)
  Magnetic Resonance Imaging and Spectroscopic Imaging of Prostate Cancer
  Cancer Investigation 2001 Vol. 19 (5) Pg. 510-523
         
  MRI provides superior visualization of prostate morphology and zonal anatomy compared to (TRUS) transrectal ultrasonography. Recently 1H magnetic resonance spectroscopic imaging (3D MRSI) have been developed which can be used for metabolic information throughout the prostate gland.
       
  With increasing expression the staging accuracy of MRI is between 75 and 90%. T2-weighted images have improved the accuracy or detection of extracapsular extension (ECE) of prostate cancer. The metabolic information from 3D MRI combined with morphologic information provided by MRI can significantly improve the localization of cancer within the prostate and provide useful information for ECE.
       
  This improved localization prior to therapy could greatly assist treatment planning for localized prostate cancer such as for the use of brachytherapy. MRI guided biopsies and MR guided therapies are future diagnostic and therapeutic modalities respectively.