Bevacizumab/high-dose chemotherapy with autologous stem-cell transplant for poor-risk relapsed or refractory germ-cell tumors.

BACKGROUND: High-dose chemotherapy (HDC) using sequential cycles of carboplatin/etoposide is curative for relapsed germ-cell tumors (GCT). However, outcomes of high-risk patients in advanced relapse remain poor. We previously developed a new HDC regimen combining infusional gemcitabine with docetaxel/melphalan/carboplatin (GemDMC), with preliminary high activity in refractory GCT. Given the high vascular endothelial growth factor expression in metastatic GCT and the synergy between bevacizumab and chemotherapy, we studied concurrent bevacizumab and sequential HDC using GemDMC and ifosfamide/carboplatin/etoposide (ICE) in patients with poor-risk relapsed or refractory disease. PATIENTS AND METHODS: Eligibility criteria included intermediate/high-risk relapse (Beyer Model), serum creatinine ≤ 1.8 mg/dl and adequate pulmonary/cardiac/hepatic function. Patients received sequential HDC cycles with bevacizumab preceding GemDMC (cycle 1) and ICE (cycle 2). The trial was powered to distinguish a target 50% 2-year relapse-free survival (RFS) from an expected 25% 2-year RFS in this population. RESULTS: We enrolled 43 male patients, median age 30 (20-49) years, with absolute refractory (N = 20), refractory (N = 17) or cisplatin-sensitive (N = 6) disease, after a median 3 (1-5) prior relapses. Disease status right before HDC was unresponsive (N = 24, progressive disease 22, stable disease 2), partial response with positive markers (PRm(+)) (N = 8), PRm(-) (N = 7) or complete response (N = 4). Main toxicities were mucositis and renal. Four patients (three with baseline marginal renal function) died from HDC-related complications. Tumor markers normalized in 85% patients. Resection of residual lesions (N = 13) showed necrosis (N = 4), mature teratoma (N = 2), necrosis/teratoma (N = 3) and viable tumor (N = 4). At median follow-up of 46 (9-84) months, the RFS and overall survival rates are 55.8% and 58.1%, respectively. CONCLUSIONS: Sequential bevacizumab/GemDMC-bevacizumab/ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the results expected in this difficult to treat population. CLINICALTRIALSGOV: NCT00936936.

Response in bone turnover markers during therapy predicts overall survival in patients with metastatic prostate cancer: analysis of three clinical trials.

BACKGROUND: The bone-forming metastases of prostate cancer result from complex stromal-epithelial interactions within the tumour microenvironment. Autocrine-paracrine signalling pathways between prostate cancer epithelial cells, osteoblasts, and osteoclasts stimulate aberrant bone remodelling, and the activity of these three cell populations can be quantitatively measured using prostate-specific antigen (PSA), bone-specific alkaline phosphatase (BAP) and urine N-telopeptide (uNTx), respectively. The purpose of the present study was to test the hypothesis that serial measurements of BAP and uNTx during therapy would facilitate monitoring of disease activity and predict the overall survival (OS) in patients with metastatic prostate cancer receiving therapy. METHODS: Radionuclide bone scan, PSA, BAP, and uNTx data were retrospectively analysed from three clinical trials in patients with metastatic prostate cancer conducted at our institution. Qualitative changes in bone scans and quantitative changes in PSA, BAP, and uNTx concentrations during therapy were correlated with OS. RESULTS: Baseline levels of BAP, but not PSA, were prognostic for OS in both androgen-dependent and castrate-resistant disease. A reduction in PSA, BAP, uNTx, or BAP/uNTx on therapy was predictive of improved OS in both patient groups. Conversely, an increase in PSA, or BAP on therapy was predictive of worse OS in both patient groups. Baseline number of lesions and response on bone scan during therapy were neither prognostic nor predictive of OS in either patient group. CONCLUSION: These observations support the concept that serial measurements of bone turnover metabolites during therapy function as clinically informative predictive biomarkers in patients with advanced prostate cancer and skeletal metastases. PSA measurements and bone scans remain essential to monitor the overall disease activity and determine the anatomic distribution of skeletal metastases.

Effect of Paget's disease of bone (osteitis deformans) on the progression of prostate cancer bone metastasis.

BACKGROUND: Patients with prostate cancer tend to die from bone metastases. Until now, no evidence has shown that Paget's disease of bone (PDB) affects the progression of bone metastasis or overall survival of patients with prostate cancer. METHODS: We searched our patient database for men who had presented with prostate cancer and PDB between June 1993 and March 2009, and identified best-matched control patients according to stage, grade, age, date of diagnosis, treatment, and race. RESULTS: Among 1346 consecutive patients with prostate cancer diagnosed before 2008, 15 were confirmed to have comorbid PDB. Twenty-six more were identified from the institutional billing search. Including the 41 best-matched controls, our total study population was 82 patients. In the Kaplan-Meier analysis, we estimated median times from diagnosis of prostate cancer to bone metastasis to be 21.5 years for those with PDB and 9.4 years for those without PDB (P=0.044). Median overall survival times were 11.8 and 9.2 years for the two groups, respectively (P=0.008). CONCLUSION: For the first time, we have obtained evidence that patients with prostate cancer and PDB have delayed time to bone metastases and improved overall survival than do patients with prostate cancer alone.

Thiazolidinediones and metformin associated with improved survival of diabetic prostate cancer patients.

BACKGROUND: The association between antidiabetic medications and the prognosis of human prostate cancer has not been explored. This study examined the impact of these drugs on the outcomes of diabetic patients with prostate cancer to provide a basis for diabetes management strategy in these patients. PATIENTS AND METHODS: Records of consecutive prostate cancer patients with coexisting diabetes mellitus type 2 who were treated at the study institution between 15 July 1999 and 31 December 2008 were reviewed. The survival, cancer pathological grade, stage at the time of diagnosis, and antidiabetic pharmacotherapy of the patients were analyzed. RESULTS: A total of 233 consecutive cases were analyzed. In Kaplan-Meier analysis, thiazolidinedione (log-rank, P = 0.005) and metformin (log-rank, P = 0.035) usage were significant predictors of improved overall survival, while insulin and insulin secretagogue usage were not significant predictors. Multivariate Cox regression analysis showed that thiazolidinedione {hazard ratio [HR] = 0.454 [95% confidence interval (CI) 0.213-0.965], P = 0.040} and metformin [HR = 0.550 (95% CI 0.315-0.960), P = 0.035] usage remained as significant predictors of favorable survival after controlling for variables including age, race, Gleason grade, and stage. CONCLUSIONS: Thiazolidinediones and metformin appear to be associated with improved overall survival of diabetic prostate cancer patients. The choice of antidiabetic pharmacotherapy may influence overall survival of these patients.

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings.

The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 x 10(6) U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen.

Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer.

The significance of apoptosis in relation to the development and progression of prostate cancer remains largely undefined. bcl-2 is an oncogene that functions by overriding apoptosis. bcl-2 expression was localized to the basal epithelial cells in the normal human prostate with the use of immunohistochemistry. Androgen-dependent and androgen-independent prostate carcinomas were evaluated immunohistochemically for bcl-2 expression. bcl-2 was undetectable in 13 of 19 cases of androgen-dependent cancers. In contrast, androgen-independent cancers displayed diffuse, high levels of bcl-2 staining (P < 0.01). In rats, steady-state levels of bcl-2 mRNA, assessed by S1 assays, reached maximum levels 10 days following castration. Addition of exogenous testosterone with, or without, flutamide demonstrated that the increased bcl-2 mRNA resulted from androgen ablation. Our findings indicate that bcl-2 expression is augmented following androgen ablation and is correlated with the progression of prostate cancer from androgen dependence to androgen independence.

Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: results of a randomized trial.

PURPOSE: Hematopoietic growth factors have been shown to ameliorate the side effects of chemotherapy. Here we assess the ability of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to increase the dose-intensity and reduce the side effects of escalated methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy. PATIENTS AND METHODS: A prospective randomized trial to compare escalated MVAC versus escalated MVAC with rhGM-CSF was conducted. All patients were treated at The University of Texas M.D. Anderson Cancer Center (UTMDACC) and had a metastatic or unresectable urothelial tumor. Forty-eight patients were randomized (25 to MVAC with rhGM-CSF and 23 to escalated MVAC alone). The clinical characteristics of the study populations were similar (ie, degree of tumor dissemination and performance status). RESULTS: The dose-intensity in the two arms of the study did not differ significantly. No difference in the frequency of bacteriologically documented infections occurred between the two study arms. CONCLUSION: The use of the hematopoietic growth factor rhGM-CSF did not result in an increased dose-intensity of escalated MVAC. The inability to increase the dose-intensity of MVAC further was a result of nonhematologic side effects of the chemotherapy. Escalation of treatment delivered at its median-tolerated dose is unlikely to result in additional therapeutic benefit for patients with common solid tumors. Future development of therapy may require the development of new agents or concepts, rather than modification of existing therapies.

Phase II trial of alternating weekly chemohormonal therapy for patients with androgen-independent prostate cancer.

Two distinct regimens of weekly chemotherapy for hormone-refractory prostate cancer were combined in an alternating schedule and tested in a Phase II trial to determine efficacy and toxic effects. Forty-six patients with hormone-refractory prostate cancer and rising prostate-specific antigen (PSA) levels entered the trial. Therapy consisted of doxorubicin (20 mg/m2/week) plus oral ketoconazole (400 mg three times a day) given at weeks 1, 3, and 5 and vinblastine (5 mg/m2/week) plus oral estramustine (140 mg three times a day) given at weeks 2, 4, and 6. No therapy was given at weeks 7 and 8. Replacement doses of hydrocortisone were administered throughout treatment to counteract potential adrenal insufficiency secondary to the ketoconazole. In 67% of patients (31 of 46), the PSA declined by 50% or greater for a minimum duration of 8 weeks (95% confidence interval, 52-80%). Among the 16 patients with measurable soft tissue disease, there were 12 responses (75%; 95% confidence interval, 47-92%). The median duration of response was 8. 4 months (1.8-14.9). The median survival for the entire group was 19 months. The median survival of PSA responders has not been reached, whereas that of nonresponders was 13 months (P = 0.010). Seventy-six percent of symptomatic patients noted improvement. Hematological toxicity was modest and was managed without growth factors. Peripheral edema (49%) and deep venous thrombosis (18%) were the most common nonhematological toxicities. The alternating weekly regimen of chemohormonal therapy is active for hormone-refractory prostate cancer, providing a high rate of symptom control, soft tissue response, and PSA decline.

Phase I study of suramin combined with doxorubicin in the treatment of androgen-independent prostate cancer.

In this study, we determined the maximum tolerated plasma concentration of suramin (within the predetermined study target range) when combined with doxorubicin in the treatment of androgen-independent prostate cancer. Twenty-four patients received suramin dosages based on proportional adjustment of the steady-state plasma suramin concentration to achieve the targeted plasma concentrations of 50-100, 101-150, 151-200, or 201-250 microg/ml. Doxorubicin (20 mg/m2) was administered i.v. over 24 h at weekly intervals. Suramin was given i.v. over 2 h twice weekly. Patients received treatment until dose-limiting toxicity or disease progression. Side effects similar to those reported for suramin and doxorubicin administered as individual agents were observed. Dose-limiting motor neuropathy developed in three patients (13%). Twelve of 24 evaluable patients (50%; 95% confidence interval, 28-71%) and 6 of 10 evaluable patients (60%; 95% confidence interval, 26-88%) had a >50% decrease of prostate-specific antigen and measurable lesions, respectively. The maximum tolerated plasma level of suramin when combined with doxorubicin was 151-200 microg/ml. Future studies on suramin combined with doxorubicin or other agents could be performed using a fixed dosing scheme with a targeted suramin steady-state plasma concentration of 200 microg/ml.

Establishment of two human prostate cancer cell lines derived from a single bone metastasis.

Human prostate cancer cell lines are particularly difficult to establish, and most existing cell lines do not exhibit features commonly seen in human prostate cancer. Most available models either grow only in vivo as xenografts or are androgen insensitive and fail to express prostate-specific antigen (PSA). The lack of functionally relevant model systems of advanced prostate cancer has limited prostate cancer research and therapy development. Of 30 processed samples derived from patients with prostate cancer, we established two cell lines (MDA PCa 2a and MDA PCa 2b) that express PSA and androgen receptor, grow in vitro, and are androgen sensitive. Cells from these lines produced tumors in nude mice when injected either s. c. or orthotopically (intraprostatic). Both cell lines were established from a bone metastasis of a patient whose cancer was exhibiting androgen-independent growth. Although both were derived from two samples of the same specimen, they have different genetic features (as assessed by karyotype analysis) and different phenotypes (e.g., morphology and growth rate). It is likely that they are distinct clones isolated by the use of different culture procedures and reflect the genetic heterogeneity of the tumor. These new cell lines are the first available derived from a bone metastasis of an androgen-independent prostatic adenocarcinoma that grow both in vivo and in vitro and have retained PSA expression and androgen sensitivity. They therefore constitute important model systems to address critical questions related to the androgen-independent growth of human prostate cancer and to the complex process of bone metastasis.

Oral cancer progression and c-erbB-2/neu proto-oncogene expression.

Monoclonal antibody PAb3 to c-erbB-2/neu protein was utilized in the immunoperoxidase staining of 86 human specimens from oral mucosa. These tissue specimens represented a spectrum from 7 normal to 9 simple hyperplasia, 15 mild dysplasia, 14 moderate dysplasia, 20 severe dysplasia and 21 squamous cell carcinoma. Our study indicated that as the cells acquire a more malignant phenotype, there was a progressive increase in neu expression. It also suggested that neu may be involved in the development of oral cancers and that its evaluation in the early stages may assist in the diagnosis and management of oral cancers.

Combination adriamycin and suramin induces apoptosis in bcl-2 expressing prostate carcinoma cells.

Bcl-2 expression has been associated with progression of prostate cancer from androgen-dependence to androgen-independence and may contribute to the relative drug-resistant phenotype typically observed in androgen-independent prostate cancer. Dunning-G rat prostate cancer cells transfected with a bcl-2 expression vector demonstrated resistance to apoptosis induced by adriamycin and, to a lesser extent, suramin. Use of adriamycin and suramin in combination, however, circumvents this bcl-2 associated drug resistance. Our findings indicate that combination drug actions may induce apoptosis in resistant malignant cell types with defective apoptotic pathways.

The bcl-2 oncogene: apoptosis and neoplasia.

Cloning of the t(14;18) translocation breakpoint resulted in the identification of a new putative oncogene, which mapped to 18q21, termed bcl-2. The t(14;18) resulted in inappropriately high levels of bcl-2 expression in follicular lymphoma. Prospective studies using mice transgenic for a human bcl-2-immunoglobulin minigene, intended to recreate the molecular features of the t(14;18), demonstrated that bcl-2 gene deregulation was oncogenic. Interestingly, overexpression of bcl-2 showed no demonstrable influence on rates of cellular proliferation. Rather, bcl-2 was found to extend cellular viability by blocking apoptosis. Recent studies with other oncogenes and tumor suppressor genes, such as c-myc and p53, have demonstrated that the deregulation of apoptosis may be of general significance in the development of multiple types of cancer and appears to be a critical event during multistep carcinogenesis. The selective induction of apoptosis in tumor cell populations is now being considered in the design of novel therapeutic interventions.

Strontium-89 combined with doxorubicin in the treatment of patients with androgen-independent prostate cancer.

We investigated the activity of a bone-targeting regimen consisting of strontium-89 and doxorubicin in the treatment of patients with androgen-independent prostate cancer. Three and 22 patients with androgen-independent prostate cancer and bone metastasis received doxorubicin at 15 mg/m(2) and 20 mg/m(2), respectively (intravenously by continuous infusion over 24 hours, once per week). All patients received strontium-89 55 µCi/kg, intravenously, every 3 months. Antitumor activity (a prostate specific antigen decrease of ≥75% from baseline) was seen in 32% of evaluable patients. Clinical benefit based on pain relief and performance improvement was achieved in 76% and 40% of patients, respectively. Strontium-89 combined with doxorubicin can be delivered with acceptable toxicities. Strontium-89 combined with doxorubicin is active in the treatment of androgen-independent prostate cancer and may be useful in future studies designed to optimize organ (bone)-specific therapies.

A phase I study of FAP (5-Fluorouracil, α-interferon and cisplatin) combined with methotrexate for the treatment of advanced urothelial malignancies.

Combination chemotherapy using 5-fluorouracil and α-interferon is active against advanced urothelial cancers. Its toxcity profile appears favorable such that addition of other active agents (i.e., cisplatin and methotrexate) may improve its therapeutic window. Our goal was to identify the starting dose of FAP (5-fluorouracil-α-interferon-cisplatin) that will permit delivery of methotrexate in patients with advanced chemotherapy-refractory urothelial cancers. This is a phase 1 study in which the dose level of FAP that permitted delivery of two doses of methotrexate in 28 days will be considered the maximum tolerated dose (MTD). This is based on experiences with MVAC chemotherapy in which only half of the patients received two doses of methotrexate in a 28 days cycle. The dose level identified as the MTD is as follows: 5-FU 500 mg/m(2) by intravenous continuous infusion daily for 5 days in weeks 1 and 4; α-interferon 5 MU/m(2) subcutaneously daily for 5 days simultaneously with 5-FU infusion in weeks 1 and 4 and thrice weekly during weeks 2 and 3; and cisplatin 25 mg/m(2) plus methotrexate 30 mg/m(2) intravenously once weekly for 4 weeks. The treatment will be repeated every 6 weeks. Most of the significant toxic effects, including mucositis, neutropenia, and thrombocytopenia, are encountered during weeks 3 and 4. This study showed that the MTD for FAP combined with methotrexate has been determined for phase II studies. Exploration of alterative regimen such as FAP in the treatment of advanced urothelial cancer is warranted. FAP has a unique mechanism of action and acceptable toxicity profile that may allow novel drug combinations and improved therapeutic efficacy.

Molecular correlates of bcl-2-enhanced growth following androgen-ablation in prostate carcinoma cells in vivo.

Androgen-independent growth of prostate cancer is correlated with expression of bcl-2. The impact of bcl-2 expression on the growth of prostate cancer cells following androgen ablation, was examined in the androgen-sensitive prostatic carcinoma cell line, LNCaP. Vector control and bcl-2 expressing LNCaP cells were grown subcutaneously in male nude mice. Tumor volume, apoptosis, and proliferation were assessed following castration. The levels of c-myc, p53, p21, bax, and bcl-2 protein were assessed by Western blotting. Bcl-2 expressing tumors exhibited a significant augmentation in growth compared to controls (p 0.01). No difference in the spontaneous rate of proliferation was observed between bcl-2 and control tumors, however, bcl-2 expressing tumors exhibited lower rates of apoptosis. Following orchiectomy the apoptotic index remained significantly lower in bcl-2 expressing tumors (p 0.002 at day 3). The proliferative index was maintained in bcl-2 expressing, but not control tumors following castration. This resulted in a significant growth advantage in bcl-2 tumors subsequent to androgen ablation (p 0.001). These changes were accompanied by alterations in the levels of gene products known to regulate the cell cycle and/or apoptosis. These results emphasize the significance of bcl-2 expression during prostate cancer progression and suggest possible mechanisms for the acquisition of androgen-independent tumor growth.

Risk factors for nasopharyngeal carcinoma.

In an effort to assess the relative importance of various risk factors of nasopharyngeal carcinoma (NPC), which includes antibodies to Epstein-Barr virus capsid antigen (anti-VCA) and early antigen (anti-EA) as well as other environmental factors, a multivariate logistic regression method was applied to analyze previously collected data from an epidemiologic study on 343 cases with NPC and 1017 neighborhood controls. Anti-VCA and anti-EA titers were found significantly associated with NPC. The relative risk increased with the increase of antibody titers. Individuals who smoked 30 or more cigarettes per day had more than 3.4 times higher risk than those who never smoked, while no increase in the risk was observed for those smoking less than 20 cigarettes per day and ex-smokers. Use of herb drugs, working under poor ventilation and nativity were also found to increase the NPC risk. In cases other than smoking 20 or more cigarettes per day and the frequent use of herb drugs, the synergistic interaction was not observed. In addition, male NPC individuals and Mainland Chinese were found to have relatively lower antibody titers as compared with female individuals or native Taiwanese.

Epstein-Barr virus-associated antibodies and serum biochemistry in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is difficult to diagnose in its early stages. It also has frequent recurrences and/or distant metastases after radiotherapy. Extensive clinical, serological and biochemical studies were done during 1980-1982 on 351 patients to aid in the diagnosis of the disease, especially with recurrence or metastasis. Seropositive rates of the antibody titers against viral capsid antigens (VCA) and early antigens (EA) of Epstein-Barr virus (EBV) in IgG and IgA classes were 41.7%-100%. They ranked, in order of frequency: anti-VCA/IgA, anti-VCA/IgG, anti-EA/IgG, and anti-EA/IgA. Mean total serum IgG and IgA levels were moderately increased in all patients. Serum GOT, GPT, alkaline phosphatase, lactate dehydrogenase and mucoprotein were elevated either alone or in combination in a few patients before treatment, in many patients with recurrence or metastases, and in all patients with liver metastasis.

The survival of patients with nasopharyngeal carcinoma.

The survival rates following treatment of 1,555 consecutive, previously untreated patients with nasopharyngeal carcinoma were studied. A 92.5% follow-up rate in 11 years is reported. Overall survival rates were 82.7% at one year, 67.4% at two years, 47.8% at five years, and 39.8% at ten years. Computer analysis revealed various factors influencing the survivals and hence prognosis. The outcomes in this series revealed five categories; clinical staging of nasopharyngeal carcinoma in five stages is, therefore, suggested.