Hormonal therapy for prostate cancer

Updates on hormonal therapy in the treatment of prostate cancer are presented. The most common therapy is to reduce testosterone to castrate levels. A dosage of 1 mg diethylstilbestrol daily prolonged survival in patients with advanced prostate cancer. The leuteinizing hormone-releasing hormone agonists have essentially replaced surgical orchiectomy in the vast majority of clinical settings; however, a major problem with the leuteinizing hormone- releasing hormone agonists has been the surge and flare of testosterone levels. If hormonal therapy is initiated early, the risk of major complications is significantly decreased. Combined androgen blockade is better than monotherapy, although there is only a small clinical benefit. When androgen deprivation is used for a short time and the normal androgen milieu is re-established, the side effects and toxicity of androgen deprivation are decreased. The major complications of androgen deprivation include hot flushes, reduction of bone mineral density, osteoporosis, and anemia. Intermittent androgen blockade might have the same benefits of total androgen suppression with fewer side effects, increased duration of androgen dependence, and less cost. The 10 steps to take when advising patients about initiation of androgen deprivation therapy are reviewed.     

Treatment of breast cancer with different antiprogestins: Preclinical and clinical studies

Treatment with antiprogestins in a new treatment modality for breast cancer. Previously, in rats with DMBA-induced mammary tumors we observed significant growth inhibitory effects of chronic treatment with the antiprogestin mifepristone (RU486). In addition, in 11 postmenopausal breast cancer patients, we observed one objective response, six instances of short-term stable disease, and four instances of progressive disease. Side-effects appeared mainly due to antiglucocorticoid properties of the drug. Increased plasma estradiol levels were observed which probably resulted from ovarian (rat) and adrenal (patients) steroidogenesis.

Combined treatment with an antiestrogen in the rat model caused additive growth inhibitory effects. Tumor inhibition after single treatment with mifepristone or tamoxifen was 90 and 75%, respectively. In contrast, when combined, tumor remission similar to that caused by LHRH-agonist treatment (50%) was observed. Even higher tumor remission was found after combined treatment with mifepristone plus LHRH-agonist (75%). In first studies in the rat model we observed significant tumor growth inhibitory effects with two new antiprogestins of seemingly greater potency which cause less unfavorable endocrine side-effects.

In conclusion: combined treatment (antiprogestin plus antiestrogen or LHRH-agonist) may be of value in endocrine therapy of breast cancer.     

Managing bone loss and bone metastases in prostate cancer patients: a focus on bisphosphonate therapy

Androgen deprivation therapy (ADT) and bone metastases are the most important risk factors for developing skeletal complications (eg, bone loss, pathologic fractures) in prostate cancer (PC) patients with locally advanced and metastatic disease. Bisphosphonates, which inhibit excessive osteoclast activity caused by ADT and bone metastases, have proven to be safe and effective in preventing skeletal complications and presently are the standard of care in patients with metastatic disease. Bisphosphonates should be considered for use in all PC patients with locally advanced disease initiating ADT for an intended duration of at least 1 year, especially those with a low baseline bone mineral density.     

Pulmonary hypertension associated with sarcoidosis

Pulmonary involvement is common in sarcoidosis, an immune-mediated inflammatory disorder that is characterized by non-caseating granulomas in tissue. Sarcoid patients with advanced pulmonary disease, especially end-stage pulmonary fibrosis, risk developing pulmonary hypertension (World Health Organization group III pulmonary hypertension secondary to hypoxic lung disease). Increased levels of endothelin (ET)-1 in plasma and bronchoalveolar lavage of some sarcoid patients suggest that ET-1 may be driving pulmonary fibrosis and sarcoidosis-associated pulmonary hypertension. Although a relationship between raised levels of ET-1 and clinical phenotype is yet to be identified, early evidence from studies of ET-1 blockade with drugs such as bosentan is encouraging. Such therapy possibly could be combined with standard anti-inflammatory agents to improve outcome.     

Androgen deprivation and other treatments for advanced prostate cancer

Among the issues discussed at this year's meeting on prostate cancer in Vail, Colorado, were several that specifically relate to the patient with advanced disease. Dr. E. David Crawford addressed the issue of the timing of hormone therapy, specifically reviewing several important trials that give a glimpse at the potential outcome of aggressive treatment in stage D1.5. The efficacy of antiandrogens, flutamide, bicalutamide, and nilutamide, when combined with chemical or surgical castration, was reviewed. Dr. Arturo Mendoza-Valdes reviewed the rationale behind intermittent (versus continuous) total androgen blockade, especially as related to quality of life. Dr. Paul Miller gave an update on the role of bisphosphonates as adjuvant therapy for prostate cancer. Also discussed was an important new agent for androgen deprivation, Abarelix, a sustained-release GnRH antagonist with low histamine-releasing potential which avoids testosterone and other hormone surge and flare.     

Prostate cancer: Re-focusing on androgen receptor signaling

Prostate cancer is the most common, non-dermatologic cancer in men. Since prostate cancer is highly associated with increased age, the incidence of this disease is expected to increase as the population ages. In its initial stages prostate cancer depends upon the actions of androgen, and androgen deprivation therapy induces tumor regression. Currently, androgen deprivation is achieved by either surgical or chemical androgen blockade. Unfortunately, nearly all prostate cancer patients develop tumors that grow despite androgen blockade and ultimately relapse. Many alterations in prostate cancer cells contribute to this state. Although chemotherapy induces short remissions in some patients, there are no curative therapies for metastatic disease. This review summarizes our current understanding in androgen signaling and the mechanisms that allow tumor cells to bypass androgen manipulation therapy. The identification of novel survival pathways and effector molecules that drive androgen independent growth is necessary to develop effective therapies for advanced prostate cancers.     

The role of oral acyclovir in the management of genital herpes simplex.

Oral acyclovir is an antiviral nucleoside analogue that has recently been released in Canada for use in selected patients with genital infections by the herpes simplex virus. First episodes of genital herpes should be treated with oral acyclovir as soon as the diagnosis is considered. Most people with recurrent genital herpes do not require systemic drug therapy. Selected patients with severe or long-lasting recurrences, recurrences associated with long prodromal periods (greater than 12 to 24 hours) or systemic complications such as erythema multiforme and eczema herpeticum may receive measurable benefit from treatment at the onset of symptoms. In most patients frequently recurrent disease can be suppressed with long-term therapy. Since long-term safety beyond 1 year has not been established, suppressive therapy should be stopped at least once per year to reassess the recurrence pattern. Acyclovir has not been adequately tested for safety in pregnancy and should not be prescribed for pregnant women unless the potential benefits outweigh the risks. Careful attention to disease severity, accurate diagnosis and exclusion of other causes of genital lesions will ensure that the drug is used only when beneficial.     

Urine Peptidomic and Targeted Plasma Protein Analyses in the Diagnosis and Monitoring of Systemic Juvenile Idiopathic Arthritis

PURPOSE: Systemic juvenile idiopathic arthritis is a chronic pediatric disease. The initial clinical presentation can mimic other pediatric inflammatory conditions, which often leads to significant delays in diagnosis and appropriate therapy. SJIA biomarker development is an unmet diagnostic/prognostic need to prevent disease complications. EXPERIMENTAL DESIGN: We profiled the urine peptidome to analyze a set of 102 urine samples, from patients with SJIA, Kawasaki disease (KD), febrile illnesses (FI), and healthy controls. A set of 91 plasma samples, from SJIA flare and quiescent patients, were profiled using a customized antibody array against 43 proteins known to be involved in inflammatory and protein catabolic processes. RESULTS: We identified a 17-urine-peptide biomarker panel that could effectively discriminate SJIA patients at active, quiescent, and remission disease states, and patients with active SJIA from confounding conditions including KD and FI. Targeted sequencing of these peptides revealed that they fall into several tight clusters from seven different proteins, suggesting disease-specific proteolytic activities. The antibody array plasma profiling identified an SJIA plasma flare signature consisting of tissue inhibitor of metalloproteinase-1 (TIMP1), interleukin (IL)-18, regulated upon activation, normal T cell expressed and secreted (RANTES), P-Selectin, MMP9, and L-Selectin. CONCLUSIONS AND CLINICAL RELEVANCE: The urine peptidomic and plasma protein analyses have the potential to improve SJIA care and suggest that SJIA urine peptide biomarkers may be an outcome of inflammation-driven effects on catabolic pathways operating at multiple sites. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12014-010-9058-8) contains supplementary material, which is available to authorized users.     

From the gene to the clinic: prostate cancer death can now be an exception?

The most significant discovery of the second half of the XXth century in the field of prostate cancer therapy is probably the observation that the human prostate, as well as many other peripheral human tissues, synthesize locally an important amount of androgens from the inactive steroid precursors dehydroepiandrosterone (DHEA) and its sulfate DHEA-S. In parallel with these observations, two important discoveries also made by our group are applied in the clinic worldwide, namely the use of LHRH (luteininizing hormone-releasing hormone) agonists to completely block testicular androgens, while, simultaneously, the androgens made locally in the prostate from DHEA are blocked in their access to the androgen receptor by a pure antiandrogen of the class of flutamide. This treatment, called combined androgen blockade, has been the first treatment demonstrated to prolong life in prostate cancer. While the first studies were performed in patients with advanced and metastatic disease, our recent data indicate a remarkable level of efficacy of the same treatment applied to localized prostate cancer, namely a 90% possibility of cure. However, in order to be able to treat localized prostate cancer, early diagnosis must be achieved. In the first large-scale randomized study of prostate cancer screening, we have demonstrated that 99% of prostate cancers can be diagnosed at the localized or potentially curable stage, using simple annual measurement of PSA (prostatic specific antigen). Today's data show that with the simple application of the available diagnostic and therapeutic tools, death from prostate cancer should be an exception.     

Recognition and treatment of response fluctuations in Parkinson's disease: review article

Summary.  Patients with Parkinson's disease (PD) by definition benefit from treatment with the dopamine precursor levodopa. However, after 5 years of therapy 50% of patients experience motor response complications (MRC's): the benefit from each dose becomes shorter (wearing-off fluctuations), more unpredictable (on-off fluctuations) and associated with involuntary movements (dyskinesias). In addition these patients suffer from fluctuations in motor function that are inherent to the disease itself. Recent findings have lead to the suggestion that hyperfunction of NMDA receptors on striatal efferent neurons, as a consequence of chronic non-physiologic dopaminergic stimulation, contributes to the pathogenesis of MRC's. In PD patients blockade of striatal glutamate receptors with several NMDA-antagonists improve MRC's. With progression of PD the severity and complexity of MRC's magnify, obfuscating their pattern and their relation to the medication cycle. Only through detailed history taking and patient education will the physician be able to clarify the situation and establish a rational, targeted approach to the treatment of patients with advanced PD complicated by motor fluctuations and dyskinesias. Received July 7, 2001 Accepted August 6, 2001 Published online September 10, 2002     

Administration of 1 alpha-OH vitamin D3 and calcium prevents bone mass loss in patients with advanced prostatic carcinoma after orchidectomy treated with complete androgenic blockade

Complete androgenic blockade used in the treatment of advanced prostatic carcinoma can be attained by administration of antiandrogens in orchidectomized patients or by combined therapy with LH-RH analogs and antiandrogens. The treatment, however, decreases the influence of both androgens end estrogens on bone tissue and may result in bone mass loss and increased propensity to fractures. The purpose of the study was to determine the influence of complete androgenic blockade on bone mass and skeletal metabolism in men with advanced prostatic carcinoma and to assess whether 1alpha-OH vitamin D3 (1alpha-OHD3) together with calcium supplementation is able to prevent bone mass loss in men treated with complete androgenic blockade. 51 patients with advanced prostatic carcinoma, with skeletal metastases, aged 44 - 86, mean 68 ys were included into a 12-month prospective study. All patients were treated with orchidectomy followed by therapy with flutamide in a dose of 750 mg daily. 26 patients were additionally given 1alpha-OHD3 in a dose of 0.5 microg/d and calcium carbonate in an initial dose of 1 g daily. It was found that the 12-month treatment with complete androgenic blockade resulted in a decrease in bone mineral density (BMD) by 8.1% in the lumbar spine, by 6.3% in the femoral neck and by 3.5% in the total skeleton. Therapy with 1alpha-OHD3 and CaCO3 caused complete inhibition of bone tissue loss in the lumbar spine and resulted in an increase in BMD by 2.2% in femoral neck and by 1.9% in the total skeleton. None of the examined patients experienced any skeletal fractures. In both groups of patients a prompt decrease in serum alkaline phosphatase activity - a marker of osteoblast activity and an increase in fasting urine calcium creatinine ratio indicating acceleration of bone resorption were found. Conclusions: in patients with advanced prostatic carcinoma treated with complete androgenic blockade acceleration of bone mass loss is observed; treatment with 1alpha-OHD3 and CaCO3 is able to prevent both trabecular and compact bone loss.     

Allergic Complications of Meningococcal Disease I—Clinical Aspects

Out of 717 patients with meningococcal disease 53 showed one or more of the three allergic complications: 47 (6·6%) developed arthritis, 12 (1·7%) developed cutaneous vasculitis, and 6 developed episcleritis. These complications, which were often multiple, occurred six to nine days after the beginning of the illness and three to six days after the start of successful antibiotic therapy. Those patients with severe systemic disease were prone to the complications.Histological and bacteriological study of the arthritis and vasculitis showed that these lesions were probably not due to persisting infection and suggested that they might be due to immune complex disease.     

Endocrine treatment of prostate cancer

Although androgen deprivation as a treatment for patients with prostate cancer was described more than 60 years ago its optimal use remains controversial. The widespread use of prostate-specific (PSA) assay has lead to earlier diagnosis and earlier detection of recurrent disease. This means that the systemic side effects of androgen deprivation and quality of life have become more important. Debates continue regarding the proper use and timing of endocrine therapy with orchiectomy, oestrogen agonists, gonadotropin hormone-releasing hormone (GnRH) agonists, GnRH antagonists, and androgen antagonists. A critical review of the literature was performed. Data support that androgen deprivation is an effective treatment for patients with advanced prostate cancer. However, although it improves survival, it is not curative, and creates a spectrum of unwanted effects that influence quality of life. Castration remains the frontline treatment for metastatic prostate cancer, where orchiectomy, oestrogen agonists and GnRH agonists produce equivalent clinical responses. Maximum androgen blockade (MAB) is not significantly more effective than single agent GnRH agonist or orchiectomy. Nonsteroidal antiandrogen monotherapy is as effective as castration in treatment of locally advanced prostate cancer offering quality of life benefits. Adjuvant endocrine treatment is able to delay disease progression at any stage. There is, however, controversy of the possible survival benefit of such treatment, including patients having PSA relapse after definitive local treatment for prostate cancer. Neoadjuvant endocrine treatment has its place mainly in the external beam radiotherapy setting. Intermittent androgen blockade is still considered experimental. The decision regarding the type of androgen deprivation should be made individually after informing the patient of all available treatment options, including watchful waiting, and on the basis of potential benefits and adverse effects. Several large studies are under way to investigate the role of adjuvant endocrine treatment in the field of early prostate cancer, intermittent androgen deprivation and endocrine therapy alone compared with endocrine therapy with radiotherapy. The real challenge, however, is to develop better means to avert hormone-refractory prostate cancer and better treatments for patients with hormone-refractory disease when it occurs.     

A role for tumor markers in therapeutic decisions after chemotherapy induction of objective remission in stage III epithelial ovarian neoplasms

The management of advanced stage ovarian carcinomas is presently based on initial surgical debulking, multiple drug chemotherapy including cisplatinum, second-look laparotomy. Such an aggressive approach has improved objective response rates and expected survival time, but no dramatic change has been demonstrated as for definitive cure percentages. Many Authors have attempted to turn an optimal objective response to chemotherapy (no residual or minimal residual disease at second-look) into a definitive cure with irradiation. Some reports show satisfactory results, but a high incidence of bowel obstructive complications has been demonstrated, probably due to multiple surgical manipulations before radiotherapy. A reliable diagnostic tool, that could help to avoid the second-look laparotomy (whose inherent role in improving survival is not assessed) should be therefore useful. The possible role of serum tumor markers determinations, for this purpose, is here discussed on the ground of a series of 20 patients affected by stage III ovarian carcinoma. Following this experience, a valuable role seems attributable to CA 125 in monitoring tumor response. Patients achieving values under 35 U/ml before second-look laparotomy showed tumor residuals in the range O-microscopic- less than 1 cm., that is, neoplastic localizations reliable for consolidation radiation therapy.     

An evidence-based approach to the management of uninvestigated dyspepsia in the era of Helicobacter pylori

OBJECTIVES: To provide Canadian primary care physicians with an evidence-based clinical management tool, including diagnostic and treatment recommendations, for patients who present with uninvestigated dyspepsia. RECOMMENDATIONS: The management tool has 5 key decision steps addressing the following: (1) evidence that symptoms originate in the upper gastrointestinal tract, (2) presence of alarm features, (3) use of nonsteroidal anti-inflammatory drugs (NSAIDs), (4) dominant reflux symptoms and (5) evidence of Helicobacter pylori infection. All patients over 50 years of age who present with new-onset dyspepsia and patients who present with alarm features should receive prompt investigation, preferably by endoscopy. The management options for patients with uninvestigated dyspepsia who use NSAIDs regularly are: (1) to stop NSAID therapy and assess symptomatic response, (2) to treat with NSAID prophylaxis if NSAID therapy cannot be stopped or (3) to refer for investigation. Gastroesophageal reflux disease can be diagnosed clinically if the patient''s dominant symptoms are heartburn or acid regurgitation, or both; these patients should be treated with acid suppressive therapy. The remaining patients should be tested for H. pylori infection, and those with a positive result should be treated with H. pylori-eradication therapy. Those with a negative result should have their symptoms treated with optimal antisecretory therapy or a prokinetic agent. VALIDATION AND EVIDENCE: Evidence for resolution of the dyspepsia symptoms was the main outcome measure. Supporting evidence for the 5 steps in the management tool and the recommendations for treatment were graded according to the strength of the evidence and were endorsed by consensus of committee members. If no randomized controlled clinical trials were available, the recommendations were based on the best available evidence. LITERATURE REVIEW: Evidence was obtained from MEDLINE searches for pertinent articles published from 1966 to October 1999. The searches focused on dyspepsia, diagnosis and treatment. Additional articles were retrieved through a manual search of bibliographies and abstracts from international gastroenterology conferences.     

Torticollis

Torticollis can be an isolated deformity or a sign of other neuromuscular disease. Underlying central nervous system or infectious disorders need to be considered and treated. In most patients, an improvement in the aesthetic disability is the primary objective. In general, an operation is indicated for the classical "congenital" muscular torticollis that does not respond to physiotherapy and forceful stretching of the restricting neck band. The mass or "tumor" of "congenital" torticollis requires no specific treatment. Operation may be delayed until age 1, but should probably be completed prior to school age. Reversal of craniofacial asymmetry is best achieved at an early age when there is maximum growth potential. Principles of surgery are (1) identification and release of all restricting bands involving the sternocleidomastoid muscle and other neck structures, (2) moving of the head and neck through a full range of motion prior to the completion of the procedure, and (3) resumption of physical therapy within 2 weeks of operation to prevent recurrent scar contracture. Various operations have been recommended, the most popular and reliable being inferior open tenotomy of the sternal and clavicular heads of the sternocleidomastoid muscle. Incisions should be placed low in the neck along skin lines and not over the clavicle in order to avoid hypertrophic scarring. Other procedures discussed are superior open sternocleidomastoid tenotomy (mastoid release), muscle lengthening procedures, and sternocleidomastoid excision. Only modest results should be anticipated in older children or adults with long-standing disease or advanced craniofacial asymmetry.     

Orchidectomy versus buserelin in combination with cyproterone acetate, for 2 weeks or continuously, in the treatment of metastatic prostatic cancer. Preliminary results of EORTC-trial 30843

This prospective randomized phase III trial compares orchidectomy as standard androgen-deprivative therapy of advanced (metastatic) prostatic cancer with treatment using the LHRH agonist Buserelin^® administered as nasal spray 3 daily doses of 400 μg, and combined with cyproterone acetate (CPA) 3 daily doses of 50 mg orally for 2 weeks initially to prevent flare-up of the disease, or continuously as complete androgen blockade. The trial was closed to entry in September 1989 when 367 patients were recruited. Patients were stratified for performance status (WHO) and metastatic status prior to randomization. According to patient and disease characteristics spreading of patients over the 3 arms was without statistical significant differences. Ineligibility was 5 and 4% of the patients were only partly evaluable. In March 1990 a first, preliminary analysis was performed. At that time 207 patients were off-study for progression or death and median follow-up was 1 yr. As to time-to-progression and survival there were no significant differences between the 3 arms. The meaning of this in regard to results of other trials with complete androgen blockade is discussed.     

Alteration of G1/S transition regulators influences recurrences in head and neck squamous carcinomas

Head-Neck Squamous Cell Carcinoma (HN-SCC) is a clinically challenging disease associated with a high mortality rate. The chemo-radiotherapy treatments that aim to preserve the organ represent the current gold standard therapy for advanced laryngeal disease, reserving surgery only for non-responsive or relapsed cases. Despite these aggressive approaches, local persistent or recurrent disease remains the primary cause of treatment failure but we still do not have known factors and/or markers able to predict the outcome of the disease and in particular the risk of local relapse. Here we address this point on a series of 54 cases of HN-SCC for whom the presence of local relapse was known. Using immunohistochemistry (IHC) analysis to evaluate protein expression and localization in the recurrence free and recurrence positive samples, we studied the expression of key cell cycle regulators including p53, p16, p27, pRB, Cyclin D1, Cyclin D3, and Stathmin. Overall by analyzing seven different cell cycle regulators we can hypothesize that the alteration of G1/S regulation represents a fundamental event in the onset/progression of HN-SCC cancers and that the associate use of Cyclin D1/p16 expression should be considered as a possible biomarker toward the identification of those patients that will probably develop a recurrent disease and thus should benefit of a more aggressive treatment.     

Antibiotic therapy in children with pertussis]

The data accumulated within the last years required revision of the indications to the use of antibiotics in treatment of pertussis. One of the aims of antibiotic therapy in pertussis was to prevent colonization of B. pertussis in the respiratory tracts. With that end in view the choice of antibiotics should be limited by those, to which the pathogen is the most sensitive i.e. erythromycin, ampicillin and augmentin. Comparative efficacy of erythromycin and ampicillin during the first 2 weeks of the disease was studied in 79 infants at the age not older than 1 year with pertussis and it was shown that erythromycin was advantageous by its therapeutic activity and less side effects. Expedience of the antibiotic therapy during the spastic period for providing a preventive effect on development of bronchopulmonary complications was studied in 201 patients with pertussis. No preventive effect of the antibiotics on development of the bronchopulmonary complications defined by the secondary bacterial flora was recorded. In the group of the patients treated with the antibiotics prophylactically (group 1) the complications were 2.6 times more frequent than in the patients treated with pathogenetic agents alone (group 2). Intrahospital pneumonia developed in 8.9 per cent of the patients in group 1 and in 1.5 per cent of the patients in group 2. Therefore, antibiotics should not be used at the late periods of pertussis for prophylaxis of secondary bacterial complications.     

Bone marrow transplantation in childhood leukaemia--experience and strategies in the Federal Republic of Germany

BMT has gained its place in the treatment of childhood leukaemia. Nevertheless, there are still many questions open. In acute lymphoblastic leukaemia children should normally be grafted in 2nd remission (CR). Some high risk cases, however, should probably be grafted in 1st CR. It is not clear whether children with late relapses benefit more from BMT than from renewed chemotherapy. Children with a relapse during maintenance therapy, however, have a better survival rate with BMT. In acute nonlymphoblastic leukaemia certain high risk patients should be grafted in 1st CR but it has still to be shown that BMT is superior to chemotherapy in such cases. It is not clear whether children with a relapse following intensive chemotherapy (such as the BFM-protocols) will benefit from BMT at all. In chronic myelocytic leukaemia, BMT in chronic phase should be performed. Thus, for the first time cure has become possible for this disease. Waiting for acceleration or even the occurrence of a blast crisis decreases the chance of survival after BMT dramatically. Since complications of BMT such as graft-versus-host reaction or severe infections are less frequent in children, relapses remain the main problem after BMT in childhood leukaemia.