Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers.

The mutation pattern of breast cancer molecular subtypes is incompletely understood. The purpose of this study was to identify mutations in genes that may be targeted with currently available investigational drugs in the three major breast cancer subtypes (ER+/HER2-, HER2+, and Triple Negative). We extracted DNA from fine needle aspirations of 267 stage I-III breast cancers. These tumor specimens typically consisted of >80% neoplastic cells. We examined 28 genes for 163 known cancer-related nucleic acid variations by Sequenom technology. We observed at least one mutation in 38 alleles corresponding to 15 genes in 108 (40%) samples, including PIK3CA (16.1% of all samples), FBXW7 (8%), BRAF (3.0%), EGFR (2.6%), AKT1 and CTNNB1 (1.9% each), KIT and KRAS (1.5% each), and PDGFR-α (1.1%). We also checked for the polymorphism in PHLPP2 that is known to activate AKT and it was found at 13.5% of the patient samples. PIK3CA mutations were more frequent in estrogen receptor-positive cancers compared to triple negative breast cancer (TNBC) (19 vs. 8%, p=0.001). High frequency of PIK3CA mutations (28%) were also found in HER2+ breast tumors. In TNBC, FBXW7 mutations were significantly more frequent compared to ER+ tumors (13 vs. 5%, p=0.037). We performed validation for all mutated alleles with allele-specific PCR or direct sequencing; alleles analyzed by two different sequencing techniques showed 95-100% concordance for mutation status. In conclusion, different breast cancer subtypes harbor different type of mutations and approximately 40 % of tumors contained individually rare mutations in signaling pathways that can be potentially targeted with drugs. Simultaneous testing of many different mutations in a single needle biopsy is feasible and allows the design of prospective clinical trials that could test the functional importance of these mutations in the future.

Results of a Phase II Placebo-controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non-small-cell Lung Carcinoma.

INTRODUCTION: Cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against MET, vascular endothelial growth factor receptor 2, AXL, ROS1, and RET was assessed in patients with non-small-cell lung carcinoma (NSCLC) as part of a phase II randomized discontinuation trial with cohorts from 9 tumor types. PATIENTS AND METHODS: Patients received cabozantinib 100 mg/day during a 12-week open-label lead-in stage. Those with stable disease per Response Evaluation Criteria in Solid Tumors version 1.0 at week 12 were randomized to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and progression-free survival (PFS) after randomization. RESULTS: Sixty patients with NSCLC who had received a median of 2 prior lines of therapy were enrolled. ORR at week 12 was 10%; 6 patients had a confirmed partial response, and no patients had a complete response. Overall disease-control rate (ORR + stable disease) at week 12 was 38%. Tumor regression was observed in 30 (64%) of 47 patients with post-baseline radiographic tumor assessments, including 3 or 4 patients with KRAS or epidermal growth factor receptor mutations, respectively. Median PFS after randomization was 2.4 months for both the cabozantinib and placebo arms. Median PFS from first dose for the entire cohort was 4.2 months. The most common grade 3/4 adverse events were fatigue (13%), palmar-plantar erythrodysesthesia (10%), diarrhea (7%), hypertension (7%), and asthenia (5%); 1 treatment-related grade 5 adverse event (hemorrhage) was reported during the lead-in stage. CONCLUSION: Cabozantinib exhibited clinical activity based on ORR and regression of tumor lesions in pretreated patients with NSCLC, including in patients with KRAS mutations.

Feasibility assessment of a chemoresponse assay to predict pathologic response in neoadjuvant chemotherapy for breast cancer patients.

BACKGROUND: For chemosensitivity and resistance assays to be clinically useful in predicting patient outcome, they should require small amounts of tissue and be highly reproducible and reliable. PATIENTS AND METHODS: Expanded tumor cells from transcutaneous biopsies of breast lesions (n=62) were tested for chemoresponse using the cell-based ChemoFx assay. Pathologic complete response (pCR) was determined on a subset of patients (n=34). Assay score and pCR were determined independently in a blinded manner. Logistic regression models were used to select predictors for response. RESULTS: Tumor cells were successfully isolated from 83.9% of patients. Chemoresponse profiles were robust and reproducible with coefficient of variance of <3%. In a limited initial patient outcome correlation, assay score of docetaxel/capecitabine significantly predicted pCR; the cross-validated model was 75% accurate. CONCLUSION: It is feasible to assess the chemoresponsiveness of small breast lesions using the ChemoFx assay to assist in choosing neoadjuvant chemotherapy for breast cancer patients.

Five-year results of a phase II trial of preoperative 5-fluorouracil, epirubicin, cyclophosphamide followed by docetaxel with capecitabine (wTX) (with trastuzumab in HER2-positive patients) for patients with stage II or III breast cancer.

We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5-fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2-positive disease) and to evaluate 5-year disease-free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5-fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 , cyclophosphamide 500 mg/m2 IV on Day 1 every 21 days) followed by 4 21-day cycles of docetaxel (35 mg/m2  days 1 and 8) concurrently with capecitabine (825 mg/m2 orally twice daily for 14 days followed by 7 days off) (wTX). For HER2-positive patients, treatment was modified by decreasing epirubicin to 75 mg/m2 and adding trastuzumab (H) in standard doses (FEC75-H →wTX-H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2-negative breast cancer and of 67% in patients with HER2-positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent-to-treat analysis, the pCR rate was 31% (37/118, 95% CI: 24-40%) in the HER2-negative patients, 24% (15/62, 95% CI: 14-37%) in ER-positive/HER2-negative patients, 39% (22/56, 95% CI: 27-53%) in the ER-negative/HER2-negative patients, and 46% (29/63, 95% CI: 34-48%) in the HER2-positive patients. The pCR rate in the 40 trastuzumab-treated patients was 53% (21/40, 95% CI: 38-67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand-foot skin reactions. One trastuzumab-treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1-2 decrements in left ventricular function; all five patients' cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease-free survival was 70% in the HER2-negative population (78% in ER-positive/HER2-negative and 62% in the ER-negative/HER2-negative patients) and 80% in the HER2-positive patients (87% in the trastuzumab-treated HER2-positive patients). At 5 years, overall survival was 80% in the HER2-negative population (88% in ER-positive/HER2-negative and 71% in the ER-negative/HER2-negative patients) and 86% in the HER2-positive patients (94.5% in the trastuzumab-treated HER2-positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5-year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended.

Incidence and Predictive Factors for Recovery of Ovarian Function in Amenorrheic Women in Their 40s Treated With Letrozole.

PURPOSE: This prospective study assessed the impact of 2 years of aromatase inhibitor (AI) therapy on the incidence of ovarian function recovery (OFR) in women age 40 to 49 with estrogen receptor-positive breast cancer who were premenopausal at diagnosis and who underwent chemotherapy-induced amenorrhea during adjuvant treatment. PATIENTS AND METHODS: Women age 40 to 49 with estrogen receptor-positive breast cancer who had ceased menstruating with adjuvant cyclophosphamide-based chemotherapy, had postmenopausal serum estradiol (E2), and had received tamoxifen for ≥ 1 year were treated with letrozole (2.5 mg) daily for ≥ 2 years. Serum follicle-stimulating hormone (FSH) and E2 were measured at baseline and over 2 years. A general linear model was used to assess serial FSH by OFR. Logistic regression was used to assess baseline predictors and OFR. RESULTS: The study enrolled 177 women (145 women age 45 to 49 years and 32 women age 40 to 44 years). Of 173 evaluable patients, 67 (39%; 95% CI, 31% to 46%) regained ovarian function; 11 of these patients (6%; 95% CI, 3% to 10%) resumed menses, and 56 of these patients (32%; 95% CI, 25% to 39%) developed premenopausal E2 without menses. Among AI-naïve patients, serial FSH significantly increased over time (P < .001), did not vary significantly by OFR status (P = .55), but showed mild evidence of a decrease after month 12 for those who resumed menses (P = .0989). Age less than 45 years and inhibin B were significant multivariable baseline predictors of OFR. CONCLUSION: These results emphasize the challenge in determining definitive menopause in women with chemotherapy-induced amenorrhea. The risk of OFR during treatment with AIs in amenorrheic women in their 40s is high, and AI therapy should be avoided in these patients.

Antimetastatic drugs in prostate cancer.

Despite the benefits of local therapy with radical prostatectomy and radiation, many patients with prostate cancer require hormonal ablation. While chemotherapy has proven efficacy when the disease progresses to androgen-independent prostate cancer, patients ultimately succumb to the disease, thus the identification of other active therapies is needed. Future treatment modalities include molecular targeted therapies. Prostate cancer has been an ideal model to study the multiple steps required in the metastatic cascade. These steps have been utilized in the development of metastasis inhibitors. This review will present promising agents that have been tested preclinically or are undergoing clinical investigation for their abilities in preventing prostate cancer metastasis. Because prostate cancer metastasizes preferentially to the bone, special attention will be given to agents that interfere with this pattern of metastasis. Specifically, the efficacy of angiogenesis inhibitors, metalloproteinase inhibitors, inhibitors of prostate cancer cell- endothelial cell interactions, and bisphosphonates will be reported. In addition, the introduction of these novel agents has raised many questions as to the relevance and optimal utilization of current clinical trial designs. Issues regarding combination therapy with chemotherapy, optimal timing of treatment with metastatic inhibitors, and the need for surrogate endpoints for molecular targeted therapies will be discussed.

The truth is out there: an overall perspective on androgen deprivation.

Androgen deprivation therapy (ADT) is a mainstay in the treatment of prostate cancer. The ideal timing, duration and composition of ADT remains undefined. At the present time, first-line therapy consists of orchiectomy, LHRH agonists, or combined androgen blockade (CAB). However, new combinations and treatment settings show promise for improving outcomes and decreasing toxicity.

Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer.

PURPOSE: There is a lack of treatments providing survival benefit for patients with metastatic triple-negative breast cancer (mTNBC), with no standard of care. A randomized phase II trial showed significant benefit for gemcitabine, carboplatin, and iniparib (GCI) over gemcitabine and carboplatin (GC) in clinical benefit rate, response rate, progression-free survival (PFS), and overall survival (OS). Here, we formally compare the efficacy of these regimens in a phase III trial. PATIENTS AND METHODS: Patients with stage IV/locally recurrent TNBC who had received no more than two previous chemotherapy regimens for mTNBC were randomly allocated to gemcitabine 1,000 mg/m(2) and carboplatin area under the curve 2 (days 1 and 8) alone or GC plus iniparib 5.6 mg/kg (days 1, 4, 8, and 11) every 3 weeks. Random assignment was stratified by the number of prior chemotherapies. The coprimary end points were OS and PFS. Patients receiving GC could cross over to iniparib on progression. RESULTS: Five hundred nineteen patients were randomly assigned (261 GCI; 258 GC). In the primary analysis, no statistically significant difference was observed for OS (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12; P = .28) nor PFS (HR = 0.79; 95% CI, 0.65 to 0.98; P = .027). An exploratory analysis showed that patients in the second-/third-line had improved OS (HR = 0.65; 95% CI, 0.46 to 0.91) and PFS (HR = 0.68; 95% CI, 0.50 to 0.92) with GCI. The safety profile for GCI was similar to GC. CONCLUSION: The trial did not meet the prespecified criteria for the coprimary end points of PFS and OS in the ITT population. The potential benefit with iniparib observed in second-/third-line subgroup warrants further evaluation.

Gemcitabine, Cisplatin, and sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscle-invasive bladder cancer.

BACKGROUND: Data support chemotherapy combined with antiangiogenic therapy in metastatic urothelial cancer (mUC) and muscle-invasive bladder cancer (MIBC). We investigated the efficacy and safety of gemcitabine, cisplatin, and sunitinib (GCS) in mUC and MIBC in parallel phase II trials. PATIENTS AND METHODS: Trial 1 enrolled 36 patients with mUC who were chemotherapy naive; trial 2 enrolled 9 patients with MIBC. The primary endpoints for trials 1 and 2 were response rate and pathologic complete response, respectively. GCS was given as first-line treatment for patients with mUC and as neoadjuvant therapy for patients with MIBC. The Simon minimax 2-stage design was used for an objective response rate in trial 1 and for the pathologic complete response rate in trial 2. RESULTS: The initial trial 1 GCS dose was gemcitabine 1000 mg/m(2) intravenously, days 1 and 8; cisplatin 70 mg/m(2) intravenously, day 1; and sunitinib 37.5 mg orally daily, days 1 to 14 of a 21-day cycle. These doses proved intolerable. The doses of gemcitabine and cisplatin were subsequently reduced to 800 and 60 mg/m(2), respectively, without an improvement in drug delivery, and the trial was closed. This lower-dose regimen was applied in trial 2, which was stopped early due to excess toxicity. Grade 3 to 4 hematologic toxicities occurred in 70% (23/33) of patients in trial 1 and 22% (2/9) of patients in trial 2. In trial 1, the response rate was 49% (95% CI, 31%-67%); in trial 2, the pathologic complete response was 22% (2/9). Due to early closure secondary to toxicity, the sample sizes of both trials were small. CONCLUSIONS: Delivery of GCS was hampered by excessive toxicity in both advanced and neoadjuvant settings.

Administration of cisplatin-based chemotherapy for advanced urothelial carcinoma in the community.

BACKGROUND: Renal dysfunction, poor performance status, and comorbidities may preclude frontline cisplatin-based chemotherapy in patients with advanced urothelial carcinoma (UC). The frequency of cisplatin-based chemotherapy administration in patients with advanced UC in community-based cancer centers is unknown. PATIENTS AND METHODS: A retrospective study was conducted to evaluate chemotherapy regimens administered to patients with the AJCC (American Joint Committee on Cancer) stage-4 UC who, from 2001 to 2010, presented to Texas Oncology Cancer Centers. Frontline chemotherapy was classified as cisplatin based, carboplatin based, nonplatinum based, and as no chemotherapy administered. RESULTS: A total of 298 patients were eligible for analysis, of whom 197 (66.1%) were men. The median age was 70 years (range, 28-97 years), and the primary sites of disease were bladder (243 [81.5%]), renal pelvis (41 [13.8%]), and ureter (14 [4.7%]). Overall, the regimens administered were cisplatin based in 107 patients (35.9%), carboplatin based in 81 (27.2%), and nonplatinum based in 25 (8.4%); no chemotherapy was administered in 71 (23.8%), and data were not available in 14 patients (4.7%). Cisplatin administration was more common in patients aged ≤70 years (62/150 [41.3%]) as opposed to >70 years (45/148 [30.4%]) (P = .05). Noncisplatin regimens or no chemotherapy were trending to be more commonly administered to patients >70 years (64.2 vs. 54.7%; P = .10). Limitations of a retrospective database study apply. CONCLUSION: A first-line cisplatin-based regimen was administered to 35.9% of patients who presented with AJCC stage 4 UC in a community-based cancer center network. Drug development focused on tolerable single-agent therapy or combination regimens without a cisplatin backbone should be a priority.

Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer.

BACKGROUND: We hypothesized that distinct biological processes might be associated with prognosis and chemotherapy sensitivity in the different types of breast cancers. METHODS: We performed gene set analyses with BRB-ArrayTools statistical software including 2331 functionally annotated gene sets (ie, lists of genes that correspond to a particular biological pathway or biochemical function) assembled from Ingenuity Pathway Analysis and Gene Ontology databases corresponding to almost all known biological processes. Gene set analysis was performed on gene expression data from three cohorts of 234, 170, and 175 patients with HER2-normal lymph node-negative breast cancer who received no systemic adjuvant therapy to identify gene sets associated prognosis and three additional cohorts of 198, 85, and 62 patients with HER2-normal stage I-III breast cancer who received preoperative chemotherapy to identify gene sets associated with pathological complete response to therapy. These analyses were performed separately for estrogen receptor (ER)-positive and ER-negative breast cancers. Interaction between gene sets and survival and treatment response by breast cancer subtype was assessed in individual datasets and also in pooled datasets. Statistical significance was estimated with permutation test. All statistical tests were two-sided. RESULTS: For ER-positive cancers, from 370 to 434 gene sets were associated with prognosis (P ≤ .05) and from 209 to 267 gene sets were associated with chemotherapy response in analysis by individual dataset. For ER-positive cancers, 131 gene sets were associated with prognosis and 69 were associated with pathological complete response (P ≤.001) in pooled analysis. Increased expression of cell cycle-related gene sets was associated with poor prognosis, and B-cell immunity-related gene sets were associated with good prognosis. For ER-negative cancers, from 175 to 288 gene sets were associated with prognosis and from 212 to 285 gene sets were associated with chemotherapy response. In pooled analyses of ER-negative cancers, 14 gene sets were associated with prognosis and 23 were associated with response. Gene sets involved in sphingolipid and glycolipid metabolism were associated with better prognosis and those involved in base excision repair, cell aging, and spindle microtubule regulation were associated with chemotherapy response. CONCLUSION: Different biological processes were associated with prognosis and chemotherapy response in ER-positive and ER-negative breast cancers.

Postsplenectomy cytomegalovirus mononucleosis is a distinct clinicopathologic syndrome.

Lymphocytosis in response to viral infection, such as infectious mononucleosis, rarely exceeds 20 x 10(9)/L in the adult population. Transfusion-acquired cytomegalovirus (CMV) mononucleosis after trauma-related splenectomy may cause prominent lymphocytosis, but the history and timing usually hint at the diagnosis. We describe a case of severe CMV mononucleosis that was acquired naturally decades after splenectomy. Together with the 2 similar cases that we reported recently, these cases all presented as initial diagnostic challenge because of a remote history of splenectomy, a prolonged febrile illness (approximately 4 weeks), marked lymphocytosis (peak 27.9 x 10(9)/L), and undetectable or weakened anti-CMV IgM antibody response. The diagnosis was eventually established through detection of circulating CMV antigen or DNA and a year or longer follow-up with serial determination of IgM and IgG antibodies. Two similar cases were also identified in the literature and reviewed. Although the impaired IgM response may confuse the diagnosis, it correlates well with recent studies showing that human blood IgM memory B cells are circulating splenic marginal zone B cells; asplenic or splenectomized individuals, irrespective of the underlying cause, have undetectable IgM memory B cells. Together, these findings suggest that distant or recent postsplenectomy CMV mononucleosis represents a distinct clinicopathologic syndrome resulting from poor control of early viremia because of the lack of both splenic filtration and the typical brisk IgM response. For the practicing clinician, recognizing these features may aid timely diagnosis and treatment.

Dose escalation of oral vinorelbine in combination with estramustine in hormone-refractory adenocarcinoma of the prostate.

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 > or = 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.

Hormonal therapy options for patients with a rising prostate-specific antigen level after primary treatment for prostate cancer.

At this time, many treatment options exist for primary androgen-deprivation therapy. "Standard" options with long-term results on outcome include orchiectomy, monotherapy with a luteinizing hormone-releasing hormone (LHRH) agonist, and combined androgen blockade using an LHRH agonist and antiandrogen. All treatments are associated with some morbidity related to the reduction of circulating testosterone. For this reason, "alternative" regimens are under active study to determine whether equal outcomes can be achieved with lesser toxicity.

The current state of hormonal therapy for prostate cancer.

Androgen deprivation therapy remains a mainstay of treatment for men with prostate cancer. New uses for hormonal therapy, including use in the adjuvant and neoadjuvant setting, are being evaluated. Prevention of the side effects of therapy has led to the development of alternative schedules and therapeutics.

Testicular cancer.

Testicular cancer remains a major success story in the realm of solid tumors. Although testicular cancer is highly treatable and curable, there are still many young men who succumb to the disease. Over the past year, important data regarding the diagnosis, treatment, and prognosis of testicular cancer have been reported. The significance of genetic and molecular alterations, such as i12p and epidermal growth factor receptor expression, remain at the forefront of research. However surgery and platinum-based chemotherapy are still the main treatment modalities. Attempts to limit chemotherapy and surgery while preserving cure rates are promising. The contribution of long-term platinum retention to the well-documented risk of late toxicity is unknown but provides a specific avenue for research. New tumor markers, such as lactate dehydrogenase isoenzyme-1, may provide a greater risk stratification. Positron emission tomography imaging may reduce the need for surgical resection posttherapy and provide a more comprehensive means of observation.

Germ cell tumors: review of selected studies from 2002.

Testicular cancer remains a major success story in the realm of solid tumors. There are still many remaining challenges in diagnosis, treatment, and prevention of long-term toxicity. Surgery and platinum-based chemotherapy, however, still encompass the main treatment modalities. Attempts to limit toxicity from both surgery and chemotherapy remain at the forefront of research. New chemotherapeutic options are available for patients with platinum-resistant disease, and stem cell transplant remains an area of active study.

Etanercept (Enbrel) administration for idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation.

Acute pulmonary dysfunction remains a frequent and severe complication of hematopoietic stem cell transplantation (SCT). Almost half of the pulmonary insults that occur in this seating are noninfectious in origin and are referred to as idiopathic pneumonia syndrome (IPS). In this series of 3 patients, etanercept (Enbrel; Immunex, Seattle, WA), a soluble, dimeric tumor necrosis factor alpha-binding protein, was administered to 3 consecutive pediatric allogeneic BMT recipients with IPS. The administration of etanercept, in combination with standard immunosuppressive therapy, was well tolerated and associated with significant improvements in pulmonary dysfunction within the first week of therapy. These data suggest that etanercept may represent a safe, non-cross-reactive, therapeutic option for patients with IPS and that clinical trials studying etanercept for this indication are warranted.

Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma.

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.