Search

Biosimilars are biologic products that are highly similar, but not identical, to a licensed reference (or "originator") biologic product. These agents have the potential to provide efficiencies and improve access to treatment for patients. Biosimilars are currently available for use in clinical practice, including oncology indications, and several more are in clinical development. Due to several key differences in their fundamental properties, production and manufacturing of biosimilars is more complex compared with that of small-molecule generic drugs. Accordingly, the generic drug approval process is not suitable or transferable to biosimilars, the approval of which involves extensive and thorough comparison with the originator biologic. Advanced practice providers play an important role in evaluating treatment options available to patients, prescribing, patient education, and product monitoring. In order to perform these tasks effectively, advanced practice providers should understand the concepts related to biosimilars in clinical practice, particularly regarding extrapolation to other indications, product labeling, interchangeability between products, and routine pharmacovigilance, among other clinical considerations. However, many health-care providers have limited awareness and minimal experience regarding biosimilars. Thus, the purpose of this review is to provide an overview of biosimilars and discuss the clinical considerations for oncology advanced practice providers concerning these therapies.

OBJECTIVES To assess the performance of the Cancer of the Prostate Risk Assessment (CAPRA) prognostic tool for freedom-from-metastases (FFM) and cause-specific survival (CSS) in patients with localized prostate cancer treated with definitive external beam radiotherapy (EBRT), and to determine whether the performance of CAPRA is influenced by androgen deprivation therapy (ADT) use or the presence of Gleason pattern 5 (GP-5). MATERIALS AND METHODS A total of 612 patients from a prospective database of 718 patients treated with dose-escalated EBRT from 1998 to 2008 who met CAPRA scoring criteria were included in the study. Performance of CAPRA and association of CAPRA score, GP-5 and short-term or long-term ADT use (STAD or LTAD, respectively) with FFM and CSS were evaluated using Cox models. The impact of ADT use on accuracy of the CAPRA-based CaPSURE model for CSS was assessed. The discriminatory ability of the CAPRA model and modified models incorporating GP-5 and ADT use were compared using the C-index. RESULTS Increasing CAPRA score correlated with worse FFM and CSS, and was prognostic for FFM and CSS for the overall cohort. CAPRA showed poorer discrimination for FFM and CSS in patients treated with EBRT+LTAD than those who received EBRT alone or EBRT+STAD. The addition of GP-5 and ADT use to CAPRA score increased the predictive accuracy of the CAPRA model for both FFM (C-index 0.809 vs. 0.779, P

Purpose/Objective(s) We sought to assess the utility of docetaxel administered concurrently with salvage radiation therapy (SRT) following postprostatectomy biochemical failure (BF). Methods and materials Men with postprostatectomy BF were accrued on a single-arm phase 2 clinical trial. SRT doses ranged from 64.8 to 70.2 Gy and were delivered in 1.8-Gy fractions to the prostate bed alone as the clinical target volume with a +1-cm uniform planning target volume expansion. The primary endpoint was progression-free survival at 4 years compared with the Stephenson nomogram estimate. Kaplan-Meier methods were used to assess late toxicity, BF, and distant metastases. An unplanned matched-pair analysis was performed with 19 patients treated with SRT alone. Results Nineteen men were accrued and treated. Median follow-up was 4.8 years. Median pre-RT prostate-specific antigen level was 0.7 ng/mL (interquartile range, 0.4-1.3 ng/mL). All 8 cycles of docetaxel were completed in 17 (89%) patients. Acute grade 1-4 toxicities were observed in 79%, 50%, 58%, and 11%, respectively. A total of 68% of acute grade 1 toxicities were related to fatigue, urinary, or bowel symptoms. For grade 2 toxicities, 76% were related to neutropenia, fatigue, or urinary symptoms. Acute grade 3 and 4 toxicities were most commonly neutropenia (84% and 100%, respectively). All late toxicities were grade 1 to 2 with 89% related to bowel or urinary function. Predicted 4-year progression-free survival was 39% and observed was 42% (90% confidence interval [CI], 24-60). Matched-pair analysis demonstrated no significant improvement in BF ( P = .96, hazard ratio, 0.98; 90% CI, 0.4-2.3) or distant metastases ( P = .09; hazard ratio, 0.3; 90% CI, 0.07-1.2), and no difference between late bowel ( P = .60) or urinary toxicity ( P = .41). Conclusions Docetaxel can safely be administered concurrently with SRT without significantly impacting posttreatment toxicity. Neutropenia was the most significant acute toxicity. Given the small sample size, no clear clinical benefit was observed. Larger studies are needed to determine the efficacy of concurrent docetaxel in this setting.

Background: Primary care providers inevitably care for prostate cancer survivors. However, few comprehensive resources exist to aid them in providing the most up-to-date and evidence-based care. To meet this clinical need, we examined and updated the Michigan Cancer Consortium prostate cancer survivorship guidelines. Methods: Using an expert panel and focus groups comprised of prostate cancer stakeholders, we updated the Michigan Cancer Consortium's 2009 Guidelines for the Primary Care Management of Prostate Cancer Post-Treatment Sequelae. Results: The guideline recommendations were modified to serve as a point-of-care resource and to facilitate care transitions between specialty and primary care. The modified recommendations were approved by the Michigan Cancer Consortium and now include the following elements: (1) patient-reported symptom assessment, (2) distinctions between medical and self-management strategies for prostate cancer treatment-related side effects, (3) recommendations for involv...

Purpose: To assess the utilization of physician extenders working in radiation oncology in an academic medical center and to identify opportunities to improve their utilization. Methods and Materials: A workload analysis and patient flow analysis were conducted on physician extenders employed by the University of Michigan Health System Radiation Oncology Department in order to better understand their utilization and impact on patient flow. Results: Nearly half (46%) of physician extender time was spent performing indirect patient care. Physician extenders performed most (84.3%) of the first encounters for follow-up appointments; however, these patients were seen independently by physician assistants (PAs) and nurse practitioners (NPs) only 51% of the time. Physician extenders perceived their utilization within the department would be improved with well-defined position goals (80%), less clerical work (40%), more involvement in treatment planning (40%), more training (40%), and more involvement with new patient consults (20%). Physicians felt the utilization of physician extenders could be improved by providing more training (33%), increased physician extender involvement in treatment planning (22%), increased physician extender involvement in new patient consults (11%), and increased autonomy (11%). Conclusions: This study highlights the importance of collecting data to allow for evaluation of PA and NP performance and utilization. We have highlighted a unique methodology for analyzing physician extender duties and workflow that could be employed by other organizations and medical practices, regardless of specialty, to examine PA and NP deployment and to identify opportunities to optimize their utilization.

The Cancer of the Prostate Risk Assessment (CAPRA) was developed to predict freedom from biochemical failure (FFBF) following radical prostatectomy (RP). Its utility following external beam radiation therapy (EBRT) has not been externally evaluated.A retrospective study of 612 patients treated with dose-escalated EBRT at the University of Michigan Medical Center.Compared to the derivation cohort, EBRT treated patients had higher-risk disease (28% with CAPRA of 6-10 vs. 5%, respectively). A total of 114 patients (19%) had BF with 5-year BF ranging from 7% with CAPRA 0-3 to 35% with CAPRA 7-10. For RT patients the risk of BF at 5-year was similar to 4 surgical cohorts for CAPRA scores 0-2 but lower for all CAPRA scores ≥ 3. The difference favoring RT increased with increasing CAPRA score reaching a 27-50% absolute improved at 5-years for CAPRA scores of 6-10. On multivariate analysis each CAPRA point increased the risk of BF (p0.0001) while Gleason pattern 5 in the biopsy also increased BF (p=0.01) and long-term androgen deprivation therapy (ADT) significantly reduced the risk of BF (p=0.015).Compared to surgical series the risk of BF was lower with dose-escalated EBRT with the greatest difference at the highest CAPRA scores.

BACKGROUND: After external beam radiation therapy (EBRT) for prostate cancer, a short interval to biochemical failure of

Bone is an important organ that is essential to adult hematopoiesis, electrolyte balance, and locomotion. Individuals who have metastatic breast cancer involving the bone are at increased risk for skeletal complications and those who have a history of early-stage breast cancer may be at increased risk for fragility fractures. Maintaining bone integrity is critical to control the morbidity and mortality associated with fractures and other skeletal complications. The bisphosphonates have been shown to be efficacious in decreasing the risk for skeletal complications in cancer and in osteoporosis. The article reviews the use of bisphosphonates in patients who have breast cancer.

BACKGROUND The current study evaluated the efficacy of oral uracil/tegafur (UFT) and leucovorin (LV) in patients with hormone-refractory metastatic prostrate carcinoma. METHODS Twenty-eight patients with hormone-refractory metastatic carcinoma of the prostate who had undergone antiandrogen withdrawal and no more than 1 prior chemotherapy treatment were enrolled on a single-institution Phase II trial. Patients were treated with oral UFT at a dose of 300 mg/m2/d and oral LV at a dose of 90 mg/day for 28 days followed by 7 days off therapy on a 35-day cycle regimen. RESULTS Twenty-six patients were evaluable for response and toxicity. There was no response by objective criteria in 9 patients with measurable disease. Four responses by prostate-specific antigen (PSA) criteria (i.e., PSA decrease by > 50%) were noted (15%) lasting a mean of 20.5 weeks. Therapy was generally well tolerated, with 2 patients developing Grade 4 toxicity (1 patient each with diarrhea and hand-foot syndrome) and 4 patients having significant Grade 3 toxicity (anemia, hyperbilirubinemia, and vomiting) (Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria). Six patients had stable disease by clinical, laboratory, and radiologic criteria for an average of 5 cycles of treatment (25 wks). CONCLUSIONS Although UFT and LV are generally well tolerated in the setting of hormone-refractory metastatic prostate carcinoma, the combination has a low level of activity. Its toxicity and activity is similar to that observed when intravenous 5-fluorouracil or capecitabine are given alone. It may be an option for further investigations in combination regimens. Cancer 2006. © 2006 American Cancer Society.

The pliability of cancer cells to mutate into several different phenotypes in an attempt to find one that will survive and colonize at the metastatic site is a tremendous "hurdle" to overcome in designing novel cancer therapeutics. New targets of therapy are essential if we are to effectively overcome the evasiveness of cancer. The interaction between the tumor cell and the surrounding microenvironment creates a vicious cycle that perpetuates disease survival and progression. The future of cancer therapy resides in the ability to focus on the recruited and exploited relationships of the cancer cell with the host environment. These therapies target cancer cell growth early and interrupt the vicious cycle that is created by the tumor cells interacting with bone components by inhibiting osteoclasts, osteoblasts, stromal cells, and endothelial cells. They alter the bone microenvironment, creating a hostile "soil" that prevents the "seed" from developing into bone metastases and represent a potential new platform for the development of prostate cancer therapeutics.

To evaluate the role of androgen deprivation therapy (ADT) and duration for high-risk prostate cancer patients treated with dose-escalated radiation therapy (RT).A retrospective analysis of high-risk prostate cancer patients treated with dose-escalated RT (minimum 75 Gy) with or without ADT was performed. The relationship between ADT use and duration with biochemical failure (BF), metastatic failure (MF), prostate cancer-specific mortality (PCSM), non-prostate cancer death (NPCD), and overall survival (OS) was assessed as a function of pretreatment characteristics, comorbid medical illness, and treatment using Fine and Gray's cumulative incidence methodology.The median follow-up time was 64 months. In men with National Comprehensive Cancer Network defined high-risk prostate cancer treated with dose-escalated RT, on univariate analysis, both metastasis (P.0001; hazard ratio 0.34; 95% confidence interval 0.18-0.67; cumulative incidence at 60 months 13% vs 35%) and PCSM (P=.015; hazard ratio 0.41; 95% confidence interval 0.2-1.0; cumulative incidence at 60 months 6% vs 11%) were improved with the use of ADT. On multivariate analysis for all high-risk patients, Gleason score was the strongest negative prognostic factor, and long-term ADT (LTAD) improved MF (P=.002), PCSM (P=.034), and OS (P=.001). In men with prostate cancer and Gleason scores 8 to 10, on multivariate analysis after adjustment for other risk features, there was a duration-dependent improvement in BF, metastasis, PCSM, and OS, all favoring LTAD in comparison with STAD or RT alone.For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of LTAD and RT provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10.

To assess the impacts of patient age and comorbid illness on rectal toxicity following external beam radiation therapy (EBRT) for prostate cancer and to assess the Qualitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) normal tissue complication probability (NTCP) model in this context.Rectal toxicity was analyzed in 718 men previously treated for prostate cancer with EBRT (≥75 Gy). Comorbid illness was scored using the Charlson Comorbidity Index (CCMI), and the NTCP was evaluated with the QUANTEC model. The influence of clinical and treatment-related parameters on rectal toxicity was assessed by Kaplan-Meier and Cox proportional hazards models.The cumulative incidence of rectal toxicity grade ≥2 was 9.5% and 11.6% at 3 and 5 years and 3.3% and 3.9% at 3 and 5 years for grade ≥3 toxicity, respectively. Each year of age predicted an increasing relative risk of grade ≥2 (P.03; hazard ratio [HR], 1.04 [95% confidence interval {CI}, 1.01-1.06]) and ≥3 rectal toxicity (P.0001; HR, 1.14 [95% CI,1.07-1.22]). Increasing CCMI predicted rectal toxicity where a history of either myocardial infarction (MI) (P.0001; HR, 5.1 [95% CI, 1.9-13.7]) or congestive heart failure (CHF) (P.0006; HR, 5.4 [95% CI, 0.6-47.5]) predicted grade ≥3 rectal toxicity, with lesser correlation with grade ≥2 toxicity (P.02 for MI, and P.09 for CHF). An age comorbidity model to predict rectal toxicity was developed and confirmed in a validation cohort. The use of anticoagulants increased toxicity independent of age and comorbidity. NTCP was prognostic for grade ≥3 (P=.015) but not grade ≥2 (P=.49) toxicity. On multivariate analysis, age, MI, CHF, and an NTCP20% all correlated with late rectal toxicity.Patient age and a history of MI or CHF significantly impact rectal toxicity following EBRT for the treatment of prostate cancer, even after controlling for NTCP.

Background Low-risk prostate cancer (PCa) patients have excellent outcomes, with treatment modality often selected by perceived effects on quality of life. Acute urinary symptoms are common during external beam radiotherapy (EBRT), while chronic symptoms have been linked to urethral dose. Since most low-risk PCa occurs in the peripheral zone (PZ), we hypothesized that EBRT using urethral sparing intensity modulated radiation therapy (US-IMRT) could improve urinary health-related quality of life (HRQOL) while maintaining high rates of PCa control. Methods Patients with National Comprehensive Cancer Network (NCCN) defined low-risk PCa with no visible lesion within 5 mm of the prostatic urethra on MRI were randomized to US-IMRT or standard (S-) IMRT. Prescription dose was 75.6 Gy in 41 fractions to the PZ + 3–5 mm for US-IMRT and to the prostate + 3 mm for S-IMRT. For US-IMRT, mean proximal and distal urethral doses were limited to 65 Gy and 74 Gy, respectively. HRQOL was assessed using the Expanded Prostate Cancer Index (EPIC) Quality of Life questionnaire. The primary endpoint was change in urinary HRQOL at 3 months. Results From June 2004 to November 2006, 16 patients were randomized, after which a futility analysis concluded that continued accrual was unlikely to demonstrate a difference in the primary endpoint. Mean change in EPIC urinary HRQOL at 3 months was −0.5 ± 11.2 in the US-IMRT arm and +3.9 ± 15.3 in the S-IMRT arm (p = 0.52). Median PSA nadir was higher in the US-IMRT arm (1.46 vs. 0.78, p = 0.05). At 4.7 years median follow-up, three US-IMRT and no S-IMRT patients experienced PSA failure (p = 0.06; HR 8.8, 95% CI 0.9–86). Two out of 3 patients with PSA failure had biopsy-proven local failure, both located contralateral to the original site of disease. Conclusions Compared with S-IMRT, US-IMRT failed to improve urinary HRQOL and resulted in higher PSA nadir and inferior biochemical control. The high rate of PSA failure and contralateral local failures in US-IMRT patients, despite careful selection of MRI-screened low-risk patients, serve as a cautionary tale for focal PCa treatments.

The division of Gleason score (GS) into three categories (2-6, 7, 8-10) may not fully use its prognostic power, as revealed by recent reports demonstrating the presence of Gleason Pattern 5 (GP5) as a strong predictor for biochemical recurrence. Therefore, we analyzed the clinical outcomes in patients treated with dose-escalated radiation therapy (RT) based on the presence or absence of GP5.Outcomes were analyzed for 718 men treated for localized prostate cancer with external-beam RT to a minimum planning target volume dose of at least 75 Gy. We assessed the impact of GP5 and that of pretreatment- and treatment-related factors on freedom from biochemical failure, freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS).At biopsy, 89% of patients had no GP5, and 11% (76/718) had GP5. There were no differences in age, comorbid illness, T stage, prostate-specific antigen, or the use or duration of androgen deprivation therapy between GS8 without GP5 and GS8-10 with GP5. The presence of GP5 predicted lower FFM (p0.002; hazard ratio [HR] 3.4 [1.7-7.1]); CSS (p0.0001; HR 12.9 [5.4-31]); and OS (p0.0001; HR 3.6 [2.0-6.5]) in comparison with GS8 (without GP5). The 8-year FFM, CSS, and OS were 89%, 98%, and 57%, respectively, for those with Gleason 8 prostate cancer without GP5 in comparison with 61%, 55%, and 31%, respectively, for those with GP5. In addition, both FFM and CSS were strongly influenced by androgen deprivation therapy given concurrently with RT. On multivariate analysis, GP5 was the strongest prognostic factor for all clinical endpoints, including OS.The presence of GP5 predicts for worse clinical behavior, which therefore needs to be accounted for by risk stratification schemes. Further intensification of local and/or systemic therapy may be appropriate for such patients.

Background: Bisphosphonates are synthetic analogs of inorganic pyrophosphates with high avidity for bone, where they bind to hydroxyapatite crystals. Bisphosphonates are effective in decreasing bone resorption, the incidence of skeletal-related events, and pain from bone metastases. These agents have recently become incorporated into the treatment regimen of patients with osteolytic and osteoblastic metastatic bone disease. Although relatively well tolerated, the initial dose(s) of intravenous aminobisphosphonates can be associated with an acute phase response, a nonspecific physiologic reaction associated with increased levels of inflammatory cytokines, fever, and flu like symptoms including fatigue, nausea, and myalgia.Objective: The purpose of this article is to provide an updated review of the literature in this field.Data Sources: A search of PubMed was performed using the key terms bisphosphonate, acute phase response, and cancer, and limited to publications in English. The published literature on acute phase response with bisphosphonate therapy was reviewed.Results and Conclusions: Approximately 40% of patients receiving aminobisphosphonates experience an acute phase response, which generally occurs only on first exposure to the drug and typically last

Purpose The primary objective of this study was to assess the feasibility and efficacy of administering etoposide/estramustine/paclitaxel in hormone-sensitive metastatic prostate cancer responding to hormonal therapy. Patients and Methods Eligible patients had metastatic prostate cancer and had received combined androgen blockade for 6-8 months with a ≤ 80% decrease in prostate-specific antigen from pretreatment. They received 4 cycles of chemotherapy consisting of estramustine 280 mg orally 3 times daily, etoposide 50 mg/m 2 orally on days 1-14, and paclitaxel 135 mg/m 2 intravenously for 1 hour on day 2 of each 21-day cycle and were then followed until time to treatment failure (TTF). Results Twenty-six patients were evaluable for response and toxicity. Median TTF was 21.7 months (range, 11.9-64.5 months; 95% confidence interval, 15.3-26.2 months). Median survival from time of initiation of hormone therapy was 5.1 years. Neutropenia was the most common grade 3/4 toxicity, occurring in 3 patients. Significant toxicities were limited to nausea, diarrhea, and febrile neutropenia in 3 patients, respectively. Conclusion The administration of paclitaxel/estramustine/etoposide in this setting is feasible and well tolerated. Although the TTF of 21.7 months by prostate-specific antigen criteria is similar to historical controls in the emergence of clinically evident androgen-independent disease after starting hormone therapy, direct comparisons cannot be made. More trials are needed to investigate the timing of chemotherapy in patients with prostate cancer.

Dural metastases have traditionally been considered a rare complication of prostate cancer; various case reports and autopsy series from the past have shown rates between 1 and 9%. Recent data from our advanced prostate cancer autopsy series, however, demonstrate a rate of dural lesions around 25%, suggesting that such complications may be more prevalent than previously reported. A case of prostate cancer, which was diagnosed after the patient presented with visual changes, is reported. Subsequent work-up revealed a lesion in the left tentorium, which was determined to be adenocarcinoma and stained positive for PSA and PAP.

BACKGROUND The primary objective of the current study was to identify the tolerable dose level of oral vinorelbine when given in combination with estramustine to men with hormone-refractory prostate cancer (HRPC). The secondary objectives were to describe the toxicities of the combined regimen in patients with HRPC and to estimate the efficacy of oral vinorelbine in combination with estramustine based on the prostate-specific antigen (PSA) response. METHODS Thirty-three patients with HRPC were treated on a 28-day cycle with estramustine at a dose of 140 mg orally 3 times a day on Days 1-3 and 8-10. Vinorelbine was given orally on Days 2 and 9. The initial dose of vinorelbine was 50 mg/m2 and was escalated to 70 mg/m2 using the time-to-event continual reassessment method. RESULTS Three of 17 patients experienced dose-limiting toxicity at the 70 mg/m2 dose level of oral vinorelbine. One patient experienced dose-limiting toxicity at a dose of 60 mg/m2 and no dose-limitig toxicities were reported at the 50 mg/m2 dose. The overall response rate by ≥50% reduction in PSA was 17.2%, (95% confidence interval, 5.9-35.8%). CONCLUSIONS Oral vinorelbine at doses of 70 mg/m2 may be safely combined with estramustine. The combination appears to have modest activity in men with advanced prostate cancer. The trial design employed the time-to-event continual reassessment method, which potentially allows for rapid accrual, a more complete assessment of toxicities, and a larger fraction of patients to be treated at an effective dose. More active regimens are needed to further evaluate the utility of this clinical trial design in patients with prostate cancer. Cancer 2006. © 2006 American Cancer Society.

The case of a 66-year-old gentleman who presented with unilateral proptosis, eye pain and partial loss of vision seven years after his original prostate cancer diagnosis is reported. MRI of the orbits revealed a 2-cm lesion in the posterolateral right orbital wall near the optic foramen with compression of the optic nerve. Metastatic orbital lesions are relatively uncommon in prostate cancer. Treatment is palliative and varies according to the time of presentation in the course of the disease. This patient's symptoms resolved after reinitiation of combined androgen blockade.

Sarcomatoid carcinomas of the prostate are rare malignancies composed of carcinomatous and sarcomatous elements. Their etiology is uncertain and may represent a single malignant process or a mixture of two distinct malignancies. We report a clinical case of a patient who presented with locally advanced disease and was treated with hormonal and cytotoxic chemotherapy, but ultimately developed distant metastasis and died of the disease. A loss-of-heterozygosity analysis of the primary and metastatic tissues provided compelling evidence that the carcinomatous and sarcomatous elements are clonally related, supporting the hypothesis that a single malignant process underlies the etiology of sarcomatoid carcinoma of the prostate.

The relation between tumor kinetics and disease progression in patients with hormone-refractory prostate cancer (HRPC) has not been well described. Biochemical recurrence of prostate cancer is characterized by detectable prostate-specific antigen (PSA) levels after treatment and occurs in approximately 30% of patients after therapy for apparent localized disease. An increase in PSA almost always occurs before clinical evidence of disease. The ability to identify early biochemical failure in patients to assess disease aggressiveness and guide changes in treatment needs to be examined. We examined serial PSA data from 249 patients with metastatic disease to assess PSA doubling time (PSADT) in hormone-naive prostate cancer (HNPC) and HRPC states. In a subset of patients, the relation of PSADT to Gleason score and survival was studied. PSADT decreased from 37.5 +/- 4.5 weeks to 15.6 +/- 1.6 weeks (mean +/- SEM) in patients with HNPC versus HRPC. In this small study, PSADT did not correlate with Gleason score, survival from start of hormonal treatment, length of time receiving hormone therapy, or survival in the HRPC state. The decrease in PSADT with disease state may help provide insight into understanding the biology of late-stage disease.

BACKGROUND The authors evaluated the combination of oral cyclophosphamide, oral prednisone, and diethylstilbestrol (DES) in patients with androgen-independent prostate carcinoma (AIPC). METHODS Thirty-seven patients with prostate carcinoma refractory to androgen ablation who had undergone antiandrogen withdrawal (if previously treated with an antiandrogen) were enrolled in the current study. They were treated with oral cyclophosphamide 100 mg per day on Days 1–20, prednisone 10 mg per day continuously, and DES 1 mg continuously, on a 30-day cycle. Warfarin 1 mg per day was given as prophylaxis for thrombosis. Patient levels of prostate-specific antigen (PSA) were monitored on a monthly basis, with imaging studies every 3 months. Patients continued to receive therapy until disease progression or the occurrence of significant toxicity. The effect of therapy on the patient's quality of life was assessed using the Functional Assessment of Cancer Therapy–Prostate. RESULTS Thirty-six patients were evaluable for response. Of the 36 patients, 15 (42%) had a 50% or greater decline in PSA levels from pretreatment levels and 1 patient (6%) with measurable disease had a partial response to therapy. The median duration of response was 4.5 months (range, 4–18 months). The overall median survival period was 16.4 months. The treatment was well tolerated, with only three patients removed from the study for toxicities associated with treatment. One patient, who had been treated for more than 24 months, developed acute leukemia. Quality of life evaluation in 17 patients showed a significant improvement in responders, whereas nonresponders had no deterioration while receiving therapy. CONCLUSIONS Cyclophosphamide, prednisone, and DES represent a well tolerated, low-cost combination therapy with significant activity in the treatment of patients with AIPC. Cancer 2003. © 2003 American Cancer Society. DOI 10.1002/cncr.11686

Prostate cancer is the most commonly diagnosed cancer among American men. The majority of patients with advanced disease have metastatic bone lesions, which are frequently very painful. These lesions tend to respond well to treatment with both nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, although careful dose titration and individualized treatment plans may be needed to achieve maximal analgesia. Opioid side effects are often transient or well controlled with additional medication. Patients with intolerable side effects may experience fewer adverse reactions with a different opioid. Palliative radiation provides pain relief in up to 80% of prostate cancer patients with single or at most a few sites of localized bone pain. Bisphosphonates, powerful inhibitors of osteoclast-mediated bone resorption, are promising new agents for the treatment of painful bone lesions in prostate cancer patients. Radioisotopes, which deliver high-dose radiation to bone lesions without significantly affecting normal bone, are highly effective in providing some degree of pain relief in up to 80% of patients with diffuse, painful bone metastases. Also, chemotherapy shows promise in alleviating pain and possibly extending survival in patients with advanced prostate cancer.

4585 Background: Prostate cancer (PCa) recurrence can be identified by biochemcial failure (BF) many years prior to clinical recurrence. A short IBF (

15 Background: The division of Gleason score (GS) into three categories (2-6, 7, 8-10), may not fully utilize its prognostic power as shown by recent reports demonstrating that the presence of Gleason Pattern 5 (GP5) is a strong adverse prognostic factor. Therefore, we analyzed clinical outcomes for patients treated with dose-escalated radiation therapy (RT) based upon the presence or absence of GP5 within the biopsy specimens. Methods: Clinical outcomes were analyzed for 718 men treated for localized prostate cancer with definitive external beam RT to at least 75 Gy. We assessed the impact of GP5 as well as pre-treatment and treatment related factors on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS). Results: Median follow-up was 64 months. At biopsy, 89% of patients had no GP5 while 11% had GP5. There was no difference in age, co-morbid illness, clinical T-stage, PSA, or the use or duration of androgen deprivation therapy (ADT) between GS8 without GP5 and GS8-10 with GP5. The presence of GP5 predicted lower FFM (p Conclusions: The presence of GP5 predicts for worse clinical behavior, which therefore needs to be accounted for by risk stratification schemes. Further intensification of local and/or systemic therapy may be appropriate for such patients. No significant financial relationships to disclose.

682–5. (16) Mao L, Lee JS, Kurie JM, Fan YH, Lippman SM, Lee JJ, et al. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst 1997;89:857–62. (17) Muller CY, O’Boyle JD, Fong KM, Wistuba II, Biesterveld E, Ahmadian M, et al. Abnormalities of fragile histidine triad genomic and complementary DNAs in cervical cancer: association with human papillomavirus subtype. J Natl Cancer Inst 1998;90:433–9. (18) Otterson GA, Xiao GH, Geradts J, Jin F, Chen WD, Niklinska W, et al. Protein expression and functional analysis of the FHIT gene in human tumor cells. J Natl Cancer Inst 1998;90:426–32. (19) Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, et al. Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci U S A 1997;94:13771–6. (20) Lee MP, Feinberg AP. Aberrant splicing but not mutations of TSG101 in human breast cancer. Cancer Res 1997;57:3131–4. (21) Sigalas I, Calvert AH, Anderson JJ, Neal DE, Lunec J. Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nat Med 1996;2: 912–7.

Intravenous bisphosphonates are widely used in the management of metastatic bone disease, as well as osteoporosis. Recent published reports have documented a possible link between treatment with intravenous bisphosphonates and osteonecrosis of the jaw. We report a case of osteonecrosis of the jaw in 1 patient with prostate cancer receiving both chemotherapy and intravenous zoledronic acid (Zometa). Bisphosphonates have been demonstrated to alter the normal bone microenvironment and appear to have direct effects on tumors as well. These changes may contribute to the development of osteonecrosis of the jaw, particularly after tooth extractions or other invasive dental procedures.