PSA relapse prostate cancer: the importance of tailored therapy

Prostate specific antigen (PSA) is an invaluable tumor marker in the detection of early prostate cancer as well as a predictor of recurrence after treatment of localized disease. Current practice entails the use of factors such as pretherapy grade, stage and PSA, PSA doubling time, nature of previous therapy and patient age and functional status for a treatment recommendation. For a PSA relapse post radical prostatectomy, radiation therapy to the prostatic fossa is a primary therapeutic consideration. With careful patient selection, about 30 to 40% of patients are rendered disease free using this approach. For patients with radiation therapy as the primary treatment for their prostate cancer, salvage prostatectomy can be considered, but is rarely feasible. Systemic therapy with hormones is standard if patients are not candidates for the above mentioned salvage local therapies or if they relapse after exhaustive local therapies. Unfortunately androgen suppressive therapy is unlikely to induce cure, or prolonged remissions in PSA relapse prostate cancer. The strategy of addition of chemotherapy or biologic therapy to androgen suppressive therapy is under active investigation. The goal of this therapy is to make an impact on the time to progression to metastatic prostate cancer and correspondingly decrease prostate cancer related mortality. Preliminary results of studies incorporating early chemotherapy in combination with androgen suppressive therapy are encouraging, with improvement in time to progression and overall survival. The evaluation of biologic agents and agents with better toxicity profiles is ongoing. This is very important to make therapy widely applicable and to enable prolonged administration especially in a disease such as prostate cancer with a relatively long natural history. Strategies of adjuvant and neoadjuvant therapy in locally advanced prostate cancer are exploring the possibility of reducing the chance of PSA relapse by treating micrometastatic disease. This review discusses the current practices in risk stratification and management of PSA relapse prostate cancer. It also highlights the major clinical trials and areas of active investigation in this field.     

Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial

Background

Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy.

Objective

To evaluate the efficacy and safety of everolimus in elderly patients (those ≥65 and ≥70 yr of age) enrolled in RECORD-1.

Design, setting, and participants

The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n = 416).

Intervention

Everolimus 10 mg once daily (n = 277) or placebo (n = 139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity.

Measurements

Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety.

Results and limitations

In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation.

Conclusions

Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.     

Matrix metalloproteinase activity and osteoclasts in experimental prostate cancer bone metastasis tissue

Previously, we and others showed that broad spectrum pharmaceutical inhibition of matrix metalloproteinase (MMP) activity reduces intraosseous tumor burden and bone degradation in animal models of bone metastasis. Herein, we used specific assays to measure net enzymatic activities of individual MMPs during colonization of bone by prostate cancer cells. PC3 cells were injected into the marrow of human fetal femurs previously implanted in SCID mice. Net MMP-9 activity in bone tissues peaked 2 weeks after injection, coinciding with a wave of osteoclast recruitment. In contrast, MMP-2 and MT1-MMP activity did not change. In vitro, co-culture of PC3 cells with bone tissue led to activation of pro-MMP-9 and increases in secreted net MMP-9 activity. Activation of pro-MMP-9 was prevented by metalloprotease inhibitors but not by inhibitors of other classes of proteases. Ribozyme suppression of MMP-9 expression in PC3 cells did not affect pro-MMP-9 activation or net MMP-9 activity and did not affect the phenotype of bone tumors. siRNA targeting of MMP-9 expression in preosteoclasts in vitro demonstrated that tumor-induced preosteoclast motility was dependent on MMP-9 expression. These data suggest that osteoclast-derived MMP-9 may represent a potential therapeutic target in bone metastasis and provide a rationale for the development of MMP-9-specific inhibitors.     

Cytoreductive Nephrectomy in Patients with Synchronous Metastases from Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

Background

The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.

Objective

To determine OS benefit of CN compared with no CN in mRCC patients treated with targeted therapies.

Design, setting, and participants

Retrospective data from patients with synchronous mRCC (n = 1658) from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were used to compare 982 mRCC patients who had a CN with 676 mRCC patients who did not.

Outcome measurements and statistical analysis

OS was compared and hazard ratios (HRs) adjusted for IMDC poor prognostic criteria.

Results and limitations

Patients who had CN had better IMDC prognostic profiles versus those without (favorable, intermediate, or poor in 9%, 63%, and 28% vs 1%, 45%, and 54%, respectively). The median OS of patients with CN versus without CN was 20.6 versus 9.5 mo (p < 0.0001). When adjusted for IMDC criteria to correct for imbalances, the HR of death was 0.60 (95% confidence interval, 0.52–0.69; p < 0.0001). Patients estimated to survive <12 mo may receive marginal benefit from CN. Patients who have four or more of the IMDC prognostic criteria did not benefit from CN. Data were collected retrospectively.

Conclusions

CN is beneficial in synchronous mRCC patients treated with targeted therapy, even after adjusting for prognostic factors. Patients with estimated survival times <12 mo or four or more IMDC prognostic factors may not benefit from CN. This information may aid in patient selection as we await results from randomized controlled trials.

Patient summary

We looked at the survival outcomes of metastatic renal cell carcinoma patients who did or did not have the primary tumor removed. We found that most patients benefited from tumor removal, except for those with four or more IMDC risk factors.     

A single-institution experience with concurrent capecitabine and radiation therapy in gastrointestinal malignancies

PURPOSE: We report our clinical experience with 32 patients receiving concurrent irradiation and capecitabine.METHODS AND MATERIALS: Medical records of patients with gastrointestinal malignancies treated with radiation and capecitabine therapy were reviewed.RESULTS: The population consisted of 20 males and 12 females, with a median age of 67.5 years (45-84 years) and adequate hepatic and bone marrow function. Histology was adenocarcinoma in all patients, except two with esophageal squamous carcinoma. Twenty-one patients received the regimen as adjuvant therapy, three received preoperative therapy, and 8 patients received therapy for palliation. The median dose of capecitabine was 1600 mg/m(2)/day (1200-2500 mg/m(2)/day) orally for 5 days per week for the duration of radiation therapy. Thirty patients received a total dose ranging from 45 Gy to 64 Gy over 4-6 weeks. Two previously radiated patients received total doses of 29.9 Gy and 46 Gy. Grade 3/4 toxicities observed were neutropenia in 3 patients and diarrhea, thrombocytopenia, fatigue, and myocardial infarction in 1 patient each. No treatment-related mortality was observed. Twenty of 21 patients (95.2%) who received adjuvant therapy continue to be in complete remission. Four of 11 (36%) evaluable patients demonstrated a response.CONCLUSION: Concurrent capecitabine and radiation were very well tolerated and warrant further investigation in prospective trials.     

In vitro interaction between amphotericin B and azoles in Candida albicans.

The use of azole prophylaxis as a measure to prevent invasive fungal infections in high-risk patients is increasing and is now the standard of care in many institutions. Previous studies disagree on whether preexposure of Candida albicans to azoles affects their subsequent susceptibility to amphotericin B (AmB). The present in vitro study indicates that azole exposure generates a subpopulation of cells that are not affected by subsequent exposure to AmB. These cells that are phenotypically resistant to AmB tolerated by most cells not exposed to azole. The percentage of cells that convert to phenotypic resistance to AmB varies with the concentration and the azole. Itraconazole is more effective than fluconazole in generating cells that are phenotypically resistant to AmB and that tolerate an otherwise lethal transient exposure to AmB. Until cells that are not exposed to fluconazole are simultaneously challenged with AmB, they are not protected to a significant extent from killing by AmB. Cells that are challenged with continuous exposure to AmB also acquire phenotypic resistance to AmB at increased frequencies by azole preexposure, but this requires that the azole be continuously present during incubation with AmB. In addition, Candida cells taken from mature colonies that are not actively growing are not susceptible to the short-term killing effects of AmB without azole preexposure. The adaptive responses of C. albicans to AmB and potentially other antifungal agents that may result from prior exposure to azoles in vitro or potentially in microenvironments in vivo that induce physiological changes may have major clinical implications.     

Routine removal of the carotid sheath as part of neck dissection is unnecessary if grossly uninvolved as seen intra-operatively

The aim of this research was to determine the pathologic invasion of the carotid sheath (CS) when found grossly uninvolved during surgery, in patients undergoing neck dissection for head and neck squamous cell carcinoma (HNSCC). A prospective study was undertaken in 70 consecutive patients with biopsy proven HNSCC, without prior history of any treatment, undergoing neck dissection, in whom the CS was found grossly uninvolved intra-operatively, were included. A total of 80 neck dissections were performed. Supra-omohyoid neck dissections for clinically N0 neck and appropriate modified radical neck dissections for clinically N+ neck were carried out. 129 CS were dissected separately and thoroughly examined by well trained head and neck pathologists for tumour infiltration and the presence of lymphatic tissue. On microscopic examination, 27 patients were N0 status and the remaining 43 (61.4%) had at least one metastatic lymph node (N+). None of 129 CS specimens show the presence of normal lymphatic tissue or metastatic tumour deposits. The authors think that avoiding resection of the CS in the absence of gross invasion by nodal disease is possible without jeopardising oncologic safety. A preserved CS might offer protection to the important neurovascular structures and reduce significant morbidity.