Second-line treatment with intravenous gemcitabine and oral etoposide in platinum-resistant advanced ovarian cancer patients: results of a phase II study.

OBJECTIVE: The outcome of advanced ovarian cancer patients has not significantly improved since the introduction of platinum. One of the major reasons for this failure is the lack of an effective second-line treatment. In this phase II trial we tested the combination of gemcitabine and etoposide in 2 different groups of patients. Group 1 consisted of patients showing disease progression or relapse within 6 months of first-line platinum-based chemotherapy. Group 2 comprised heavily pretreated patients showing progression during the last chemotherapy attempt. METHODS: Thirty-four patients were enrolled. Gemcitabine was administered at a dose of 1,000 mg/m(2) on days 1 and 8 and etoposide was administered orally at 100 mg/day on days 8-12 for 6 courses. RESULTS: Eighteen patients (52.9%) had an objective response and the median duration of the response was 10.3 months. Our chemotherapy regimen showed a low toxicity and good patient compliance. In 5 patients the treatment had to be delayed and in only 2 patients it was discontinued. CONCLUSIONS: The combination of gemcitabine and oral etoposide seems to be a safe and effective second-line treatment for platinum-resistant ovarian cancer patients. Additional data on larger series are warranted to better define the activity of this combination regimen.

Prognostic value of estrogen receptor and Ki-67 index after neoadjuvant chemotherapy in locally advanced breast cancer expressing high levels of proliferation at diagnosis.

PURPOSE: Breast cancers expressing high levels of Ki-67, a nuclear marker of cell proliferation, are associated with worse outcome. Recent data from neoadjuvant studies indicate that a single measurement of the nuclear proliferation marker Ki-67 in breast carcinoma during neoadjuvant therapy is strongly predictive of long-term outcome. Secondly, recent literature data indicate that prognostic evaluation with Ki-67 may be better after pre-surgical therapy. A retrospective study from a prospectively maintained clinical database to compare the predictive and prognostic significance of biological markers, assessed before and after neoadjuvant chemotherapy, in locally advanced breast cancer, was performed. PATIENTS AND METHODS: The following parameters were considered before and after chemotherapy for their relationship with treatment response and disease-free survival in 64 patients with locally advanced breast cancer: clinical stage, clinical and pathological lymph node involvement, Ki-67, estrogen receptor (ER), progesterone receptor (Pgr), Her2, tumor grade, clinical response, type of surgery performed, and number of chemotherapy cycles administered. The expression of Ki-67 was assessed using immunohistochemistry in pre-therapy tru-cut and post-therapy surgical excision specimens after neoadjuvant chemotherapy; only patients with breast tumors expressing high baseline Ki-67 (≥ 15%) were included in the analysis. In addition, the correlation between pre-chemotherapy biological markers and clinical and pathological response was reported. RESULTS: Post-chemotherapy Ki-67 proliferation index decrease, pre-chemotherapy ER expression and post-chemotherapy ER expression were the only significant prognostic factors adversely influencing disease-free survival in univariate analysis. Her2 overexpression was the only factor to impact on the clinical response. CONCLUSIONS: Post-treatment Ki-67 and ER status were predictors of outcome for patients with locally advanced breast cancer and a high pre-chemotherapy proliferation index.

Evidence for an important role of DNA pyridyloxobutylation in rat lung carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: effects of dose and phenethyl isothiocyanate.

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), selectively induces lung tumors in F344 rats. NNK is metabolically activated to intermediates that methylate and pyridyloxobutylate DNA. To explore the importance of pyridyloxobutyl DNA adducts in NNK-induced rat lung tumorigenesis, the first study in this report examined levels of these adducts in whole lung and pulmonary cells of F344 rats treated with different doses of NNK (0.3, 1.0, 10.0, and 50 mg/kg; 3 x weekly for 2 weeks). Pyridyloxobutyl DNA adducts were highest in Clara cells compared to alveolar Type II cells, alveolar macrophages, and small cells, suggesting that enzymes involved in the formation of the pyridyloxobutylating species are concentrated in Clara cells. When we compared lung tumor incidence at the different doses of NNK (S. A. Belinsky et al., Cancer Res., 50: 3772-3780, 1990) versus pyridyloxobutyl DNA adducts in Type II cells, we observed a significant correlation. Because NNK-induced lung tumors arise from the Type II cells, this suggests an important role for pyridyloxobutyl DNA adducts. In the second study presented in this report, we examined the effect of dietary phenethyl isothiocyanate (PEITC), an inhibitor of lung tumor induction in F344 rats by NNK, on O6-methyldeoxyguanosine (O6-mG) and pyridyloxobutyl DNA adducts in whole lung and lung cells of F344 rats treated with NNK. F344 rats were fed control or PEITC-containing diets (3 micromol/g diet) before and throughout NNK treatment (1.76 mg/kg, three times weekly for 4, 8, 12, 16, or 20 weeks). PEITC inhibited formation of pyridyloxobutyl DNA adducts in whole lung and all lung cells except macrophages. There was also inhibition of O6-mG, but it varied with cell type and length of NNK treatment. Overall, PEITC treatment decreased pyridyloxobutyl DNA adducts by 57% in Clara cells, 51% in Type II cells, 40% in small cells, and 44% in whole lung. PEITC treatment decreased O6-mG levels by 52% in Clara cells, 19% in Type II cells and small cells, and 36% in whole lung. These results support the hypothesis that PEITC inhibition of NNK-induced lung tumors is a result of decreased metabolic activation and DNA binding of NNK. The 50% reduction of pyridyloxobutyl DNA adducts in Type II cells agreed well with the 50% reduction of NNK-induced lung tumors by PEITC. Because NNK-induced tumors arise from Type II cells, these results suggest an important role for pyridyloxobutyl DNA adducts in NNK-induced rat lung tumorigenesis.

Detection of O6-methyldeoxyguanosine in human placental DNA.

A monoclonal antibody specific for O6-methyldeoxyguanosine (O6-MedGuo) was developed. When used in a competitive enzyme-linked immunosorbent assay, 50% inhibition of binding was achieved with 0.51 pmol O6-MedGuo. When the competitive enzyme-linked immunosorbent assay was coupled with high-performance liquid chromatography, 2 mg of DNA could be analyzed giving a lower limit of detection of 0.5 mumol O6-MedGuo/mol deoxyguanosine. This assay was used to test for O6-MedGuo in DNA from placentas of smoking and nonsmoking women. Two of 10 DNA samples from smoking women and three of 10 from nonsmoking women had detectable concentrations of O6-MedGuo. Concentrations ranged from 0.6 to 1.6 mumol O6-MedGuo/mol deoxyguanosine. Activity of O6-alkylguanine DNA alkyltransferase was also measured. There was no apparent relationship between O6-alkylguanine DNA alkyltransferase activity and O6-MedGuo concentrations in the 20 subjects, nor did mean O6-alkylguanine DNA alkyltransferase activity differ between the two groups. Although no apparent relationship between smoking history and O6-MedGuo concentration was found in this preliminary study, this is the first report of a structurally identified DNA adduct in human placenta.

Medical treatment of advanced renal cell carcinoma: present options and future directions.

The treatment of patients with metastatic renal cell carcinoma (MRCC) continues to be disappointing. A large number of hormones, chemotherapeutic agents and combinations have been tested with poor and non-reproducible results. Among the immunological treatments investigated in MRCC, the best results have been claimed with interferons (IFNs) and interleukin-2 (IL-2) and, although no randomized studies have shown higher activity than cytotoxic drugs, hormones or even no treatment, many oncologists feel it justified to consider these biologic agents the treatment of choice for this disease. Of patients treated with alpha-IFN, 15-20% achieve an objective remission and 3-5% achieve a long-lasting complete response. No substantial increase of the therapeutic activity of alpha-IFN was produced by combination with chemotherapeutic agents and gamma-IFN or tumour necrosis factor. High doses of IL-2 with or without lymphokine-activated killer cells led to successful results in about 20-30% of patients with 5-10% complete responses. More recently, less toxic regimens with lower doses of IL-2 alone or combined with alpha-IFN produce similar response rates. Many studies have clarified the importance of prognostic factors in patient selection for response and survival during treatments with IFNs and IL-2. Good performance status, a long interval from diagnosis to treatment, and only one site of disease seem to be the most important predictors for survival. Both IFNs and IL-2 appear to possess encouraging antitumour activity in patients with favourable prognostic factors, but further studies are needed to identify the treatment of choice, the optimal dose regimen and route of administration in this subgroup of patients. Patients with poor prognosis should be encouraged to enter controlled studies aimed to evaluate investigational drugs and new therapeutic methods.

Suramin-induced growth inhibition and insulin-like growth factor-I binding blockade in human breast carcinoma cell lines: potentially related events.

Suramin, a polyanionic drug used in the treatment of trypanosomiasis and onchocerciasis, inhibits growth factor-induced mitogenesis in several human tumours. We have investigated the effect of suramin on human breast cancer cell lines (HBCCL). By cell counts and thymidine incorporation we found that 50 to 400 micrograms/ml suramin inhibits the proliferation of HBCCL in a dose-dependent and reversible fashion (ID50 approximately 200 micrograms/ml for MCF-7 and MDA-MB 231). Radioreceptor and affinity cross-linking assays showed that suramin was also able to reduce the binding of insulin-like growth factor I (IGF-I) to its receptor (40-50% inhibition at 100 micrograms/ml). Our results indicate that the drug does not affect the IGF-I receptor (IGF-I-R), but binds directly to the IGF-I peptide. In conclusion, the strict correlation observed between suramin inhibition of proliferation and IGF-I binding on HBCCL suggests a possible therapeutic role for this molecule as an antineoplastic drug in human breast tumours.

Carboplatin in advanced hormone refractory prostatic cancer patients.

25 patients with measurable or evaluable metastatic prostate cancer, progressive after hormonal treatment, were treated weekly with carboplatin 150 mg/m2 intravenously. The weekly schedule allowed higher dose intensity carboplatin administration with respect to the common monthly cycles. Toxicity was manageable even in elderly patients with extensive bone metastases and consisted primarily of myelosuppression. 4 out of 24 evaluable patients (17%) had a partial response and 12 (50%) had disease stabilisation. The median response duration was 7 months. Prostate-specific antigen and prostatic acid phosphatase serial values showed a correlation with disease response in only 47 and 50% of patients, respectively. These results suggest that carboplatin possesses a moderate but definite activity in prostate cancer patients.

Lonidamine in metastatic breast cancer.

Lonidamine belongs to a new class of antineoplastics agents, since it does interfere with cell energy processes. When administered as single agent in metastatic breast cancer, it produces moderate therapeutic effects. The pattern of toxicity includes myalgias, asthenia, testicular pain, and gastrointestinal discomfort. No myelosuppression was demonstrated in phase I-II studies. Since the peculiar mechanism of action and side effects are not overlapping with those of standard chemotherapeutic agents, combination of lonidamine with chemotherapy is currently under investigation in advanced breast cancer. Moreover, the potentiation of radiotherapy by lonidamine could be of interest in palliating symptomatic lesions from breast cancer.

Modulation of carcinogen-induced polyoma DNA-replication by organoselenium and organosulfur chemopreventive agents.

Both chemical and physical carcinogens are potent inducers of asynchronous replication of various DNA tumor viruses. Employing H3 cells that carry an integrated copy of polyoma virus we have evaluated potential effects of known chemopreventive agents on carcinogen-induced polyoma DNA replication. The ability of well established organoselenium and organosulfur chemopreventive agents, in laboratory animals, to modulate polyoma DNA replication induced by AMMN or NNKOAc which are direct acting carcinogens derived from the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was examined. We demonstrate that both benzyl selenocyanate (BSC) and benzyl isothiocyanate (BITC) are capable of reducing the level of polyoma DNA replication induced by NNK-model compounds. BITC also reduced the transcriptional activity of polyoma sequences as measured through chloramphenicol-acetyl-transferase (CAT) assays using the polyoma regulatory region cloned upstream of the CAT gene. These results suggest that the mechanisms by which BSC and BITC exert their protective effects involve changes in the expression of cellular proteins which regulate transcription and replication of polyoma DNA sequences.

Inhibition of pkc and pka by chemopreventive organoselenium compounds.

Numerous efficacy studies in rodents revealed that 1,4-phenylenebis(methylene)-selenocyanat (p-XSC) is a more effective chemopreventive organoselenium compound and less toxic than benzyl selenocyanate (BSC) or the inorganic compound Na2SeO3. To explore mechanisms which mediate chemopreventive activities of p-XSC we have tested its effect on protein kinase A and C using in vitro and cell culture systems. While p-XSC did completely inhibit PKC and PKA activity, BSC was less active and Na2SeO3 had no effect. Comparative EC,, revealed values of 0.1, 1 and > 10 mu M for p-XSC, BSC and Na2SeO3, respectively. p-XSC was also capable of inhibiting protein phosphorylation in cultures of primary human fibroblasts and altered morphology of rat fibroblast (R6) cells. When combined, sub-optimal doses of p-XSC and staurosporine yielded an additive effect on cell morphology. The ability of p-XSC and BSC to inhibit protein kinase A and C activities may in part account for the mechanism(s) by which these agents mediate their chemopreventive effects.

Breast-cancer in the elderly - detection and treatment modalities in 341 women.

Elderly cancer patients are generally excluded from entry to clinical trials;and often managed inadequately or based on individual experience. We have retrospectively determined tumor detection modality, diagnostic and staging work-up, delay in referral and therapeutic approaches in 341 women with breast cancer aged over 70 years. Fifty-eight per cent of patients were in the 70-75 group of age. Our data suggest that tumor is detected during medical visit or hospitalization for reasons other than breast cancer in 63.1% elderly women with 74.1% of tumors diagnosed on stage I+II disease; the interval between patient's awareness of a breast nodule and first diagnostic and/or therapeutic intervention was less than 3 months in 51.4% and between 3 and 6 months in 20.7% of patients. Most of our patients received adequate treatment although in 18.6%, 26.8% and 18.2% of stage Il, III and IV respectively systemic treatment was not administered after surgery. A large proportion (22.3%) of patients received Halsted mastectomy and only 11.1% conservative surgery. We suggest breast examination should be encouraged, screening program should be extended after the age of 70 years and systemic treatment should be evaluated in elderly patients.

Insulin-like growth factor-I (IGF-I) and IGF-binding proteins blood serum levels in women with early- and late-stage breast cancer: mutual relationship and possible correlations with patients' hormonal status.

The pathogenesis and progression of breast cancer involve complex interactions between hormones and polypeptide growth factors such as insulin-like growth factor-I (IGF-I). IGF-I has been found in stromal fibroblasts derived from malignant and benign breast tissue and it is a mitogen for several breast cancer cell lines. It circulates bound to specific high-affinity binding proteins, which could act as either positive or negative modulators of tumorigenesis. This study has been addressed to characterize IGF-I and its binding proteins in the serum of 85 unselected patients with early breast cancer. The IGF-I concentration was assessed by radioimmunoassay of 69 out of 85 samples before and after dissociation of the IGF-I and IGF-binding protein (IGF-BP) complex whereas IGF-BP of all 85 sera were analyzed by Western ligand blotting; estradiol and progesterone were measured by radioimmunoassay in native serum samples. In our study no differences in IGF-I serum levels between pre- and post-menopausal patients were observed. Patients with higher estradiol and progesterone serum levels did not present different IGF-I concentrations compared to patients with lower serum levels. Furthermore, IGF-I median values were not found to depend on estrogen receptor (ER) status. A heterogeneous quali-quantitative molecular pattern of binding proteins was detected: IGF-BP3 and IGF-BP1 were the most and the least expressed respectively. No correlations between ER status, or parameters related to the hormonal status, and IGF-I or binding proteins expression were observed. No significant differences in IGF-I concentration and IGF-BP expression were observed between cancer patients and a control group matched for age and menopausal status. Finally, preliminary collection of 20 sera derived from patients with late breast cancer was analyzed for IGF-I and its binding proteins content.

Prognostic factors for survival in patients with advanced renal cell carcinoma treated with interleukin-2 and interferon-alpha.

A group of 73 patients with advanced renal cell carcinoma, treated in different phase II trials with interferon alpha and/or interleukin-2, have been evaluated to identify potential baseline prognostic factors predicting their survival. The eligibility criteria were very similar across studies and included ECOG performance status < or = 2, measurable or evaluable disease and no CNS metastases. The overall response rate was 8%. The overall survival was 33% at 2 years and 18% at 1 year. In the univariate analysis three prognostic factors were correlated with disease outcome: ECOG performance status (0 versus > or = 1), time from diagnosis to treatment (< or = 12 months versus > 12 months) and number of metastatic sites (1 versus > or = 2). Multivariate analysis identified ECOG performance status and number of metastatic sites as important prognostic factors for survival. The true impact on patient survival of the selection of patients rather than the treatment itself should be evaluated in controlled trials.

Suramin/epidoxorubicin association in hormone-refractory prostate cancer: preliminary results of a pilot phase II study.

PURPOSE: Previous studies indicate that suramin may be an active agent for treating hormone-refractory prostate cancer. However, antitumour responses were observed in initial experiments only when plasma suramin concentrations were maintained in excess of 250 micrograms/ml. Dose-limiting toxicity, especially neurological toxicity, is directly related to the duration of exposure and sustained plasma drug concentrations of 300 micrograms/ml or more. Combination with other agents such as epidoxorubicin, a drug with demonstrable activity in metastatic prostatic carcinoma, could be more effective and allow reduced suramin doses, while maintaining the suramin antitumor effect; this could make suramin therapy more feasible. On the basis of preclinical synergistic activity for combined suramin/doxorubicin in prostate cancer cell lines, a pilot study in patients with metastatic hormone refractory prostate cancer was performed. MATERIALS AND METHODS: Ten patients with hormone-refractory prostate cancer received a fixed dosing scheme of suramin infusion in combination with weekly epidoxorubicin at 25 mg/m2. Therapy was discontinued for dose-limiting toxicity or progressive disease. RESULTS: None of the ten patients achieved a prostate-specific antigen reduction of more than 50% and no objective responses were observed in any patient. Dose-limiting toxicity was observed in four patients: grade 3 neurotoxicity was observed in three patients and grade 3 nephrotoxicity in one patient. CONCLUSIONS: Suramin/epidoxorubicin association, despite the encouraging preclinical results, was not able to improve the antitumour activity of suramin and showed significant toxicity. The results achieved in our study, although in a small number of patients, seem to suggest that this regimen cannot be recommended for use in the treatment of metastatic hormone-refractory prostate cancer.

Effects of dihydrotestosterone and hydroxyflutamide on androgen receptors in cultured human breast cancer cells (EVSA-T).

The purpose of our study was to evaluate the effects of 5 alpha-dihydrotestosterone (DHT) and hydroxyflutamide (HF), alone or in combination, on androgen receptor (AR) dynamics and on cellular growth in cultured breast cancer cells (EVSA-T). The incubation of cells with DHT increased the concentration of nuclear AR after 24 and 48 h. HF was also able to promote the nuclear accumulation of AR after 24 and 48 h of treatment. When HF-treated cells are incubated with DHT, the nuclear AR concentration is lower than that found in cells treated with DHT alone. We conclude that HF acts by increasing nuclear accumulation of receptor-antiandrogen complexes. Moreover, DHT stimulates cell growth while HF has an inhibitory effect. Thymidine incorporation in cells also increased after DHT treatment and decreased after HF incubation. The HF-induced inhibition of cell growth persisted both after renewal of the medium and after the addition of DHT to cultures. It may be hypothesized that either DHT is converted to inactive metabolites or that HF exerts a persistent inhibitory effect. In the latter case, the antiandrogen action of HF could be exerted by retention of high levels of antiandrogen in cells or by such a depressed protein synthesis that the renewal of growth is slower than the 48 h period studied.

In vivo manipulation of human breast cancer growth by estrogens and growth hormone: kinetic and clinical results.

Since 1983, a series of experimental and clinical studies have been carried out on the possibility of enhancing the chemotherapy effectiveness in breast cancer by expanding the fraction of cycling cells. Theoretically estrogens should recruit breast cancer cells and this fact should result in a higher killing efficiency of antiproliferative drugs. Actually it has been clearly shown, by means of the thymidine labeling index and primer-dependent alpha-DNA polymerase assay, that low doses of diethylstilbesterol are able to increase the tumor proliferative activity of human breast cancer in vivo (estrogenic recruitment). Three randomized trials have been carried out (one in locally advanced and two in metastatic breast cancer) comparing conventional polychemotherapy vs chemotherapy with estrogenic recruitment. Only limited advantages have been observed in these trials. Searching for new modalities of kinetic manipulation of tumors, recombinant human growth hormone has been employed in a pilot study: the preliminary results indicate that it largely enhances tumor proliferative activity, suggesting the possibility of employing a growth factor system to increase chemosensitivity.

Dexamethasone and suramin inhibit cell proliferation and interleukin-6-mediated immunoglobulin secretion in human lymphoid and multiple myeloma cell lines.

Uncontrolled growth of neoplastic cells and unregulated production of immunoglobulin are major components of the morbidity and mortality of multiple myeloma. Suramin, a polysulfonated napthylurea, has antitumor activity in a number of malignancies, but also significant dose-related toxicity. Suramin has been reported to have major antiproliferative effects in a variety of lymphoid cell lines. Glucocorticoids have long been recognized to have activity in lymphoid malignancies and multiple myeloma while IL-6 has been reported to be an autocrine growth factor for multiple myeloma. This study examines growth inhibition and inhibition of IL-6-mediated secretion of immunoglobulin in human lymphoid and myeloma cell lines by dexamethasone and suramin. Dexamethasone and suramin show synergistic inhibition of cell proliferation at their IC10 concentrations. IL-6-mediated immunoglobulin secretion is also inhibited by both dexamethasone and suramin in an additive fashion. Both dexamethasone and suramin induce apoptosis of lymphoid cell lines, and suramin inhibits the binding of IL-6 to its receptor in a multiple myeloma cell line. These findings suggest that the synergistic growth inhibitory activities of dexamethasone and suramin may be related to induction of apoptosis by both agents and inhibition of IL-6-mediated autocrine growth stimulation and immunoglobulin production. These results indicate that the combination of low-dose suramin (in concentrations not associated with significant clinical toxicity) and dexamethasone merit further study in the treatment of myeloma or lymphoid malignancies.

Use of long-acting somatostatin analog, lanreotide, in neuroendocrine tumors.

Somatostatin and its analogues have been reported highly effective in reducing the clinical syndrome in endocrine tumours. The effects of a long-acting analogue of somatostatin, lanreotide, were evaluated in 10 patients with neuroendocrine tumours. In patients with carcinoid tumour, a relief of flushing was achieved in 7 of 8 patients, of diarrhoea in 7 of 7 patients and of bronchoconstriction in 2 of 2 patients. In 5 of 8 patients there was a decrease of more than 50% of 5-hidroxyindolacetic acid excretion. The activity on tumour size was assessed in all the patients. No objective responses were observed. The tolerance to lanreotide was excellent. For the high symptomatic effect and mild toxicity lanreotide seems to be an appropriate treatment in symptomatic patients.

Low activity of circadian continuous fluorodeoxyuridine (fudr) chemotherapy in poor-prognosis metastatic renal-cancer.

Thirteen patients with progressive metastatic renal cell carcinoma were treated with circadian continuous Fluorodeoxyuridine (FUDR) infusions. The drug was delivered according to the variable rate infusion of Hrushesky protocol. All patients had previously received and failed systemic treatment and presented more than one metastatic site. The toxicity was low, however, no objective responses were observed. Despite previous reports of activity of FUDR in metastatic renal cancer, we suggest that the present regimen cannot be recommended in poor prognosis metastatic renal cancer.

Assessment of response to carboplatin in patients with hormone-refractory prostate cancer: a critical analysis of drug activity.

The clinical presentation of prostate-hormone refractory tumours in 90% of patients is characterised by sclerotic bone metastasis which is not assessable by classic phase II response criteria. Restriction of investigational study of new agents to the minority of patients, with bidimensionally measurable lesions, assessable by conventional WHO response criteria, has been criticised because such cases may represent a highly selected tumour cell population. To circumvent this problem, a variety of response criteria have been proposed. However, prostate specific antigen (PSA) levels have become an integral component, used singly or in combination with other markers of response evaluation. As a result, different response proportions could also be reported using the same single agent in this category of patients. This study repors a different evaluation of carboplatin activity by using WHO, NPCP modified criteria and PSA post-therapy decline as measures of carboplatin activity. It is suggested that treatment efficacy in this category of patients wold be more correctly measured by the proportion of patients who "fail treatment" after a reasonable number of therapy courses, rather than those achieving a conflicting definition of "objective response". Finally, in hormone refractory prostate cancer PSA post therapy declines may represent a measure of treatment efficacy and can be used as a surrogate end point for clinical phase II trials.