Routine interval computed tomography to detect new soft-tissue disease might be unnecessary in patients with androgen-independent prostate cancer and metastasis only to bone

OBJECTIVE: To identify patients with androgen-independent prostate cancer (AIPC) with bone metastasis and no soft-tissue metastases at the time of protocol enrollment, and analyse their disease progression by computed tomography (CT), bone scan, and prostate-specific antigen (PSA) level to determine the utility of routine interval CT in such patients. PATIENTS AND METHODS: Bone is the most common metastatic site in patients with AIPC and the only site of metastatic disease for many; because some with initial bone metastasis eventually develop soft-tissue disease, many clinical trials use routine CT to monitor for the latter as a sign of disease progression, but the actual incidence of new soft-tissue metastases is unknown and the role of routine interval CT in monitoring for disease progression, especially for asymptomatic patients, is unclear. Thus we reviewed 175 cases of metastatic AIPC from three randomized phase II clinical trials (docetaxel/thalidomide, docetaxel/vaccine, and ketoconazole/alendronate) at the National Cancer Institute between 1995 and 2004. The patients' PSA levels were assessed every 4 weeks, and CT and bone scans were done every 2-3 months. We retrospectively identified patients with bone metastasis only and examined subsequent CT for the occurrence of soft-tissue disease. For patients with progressive disease, we also examined bone scan and PSA progression. RESULTS: Of 175 patients with metastatic prostate cancer, 105 (60%) had bone metastasis only, 12 (6.9%) had soft-tissue metastases only, and 58 (33.1%) had both bone and soft-tissue metastases. The median (range) follow-up was 8 (1-44) months for the 105 patients with bone metastasis only. During that time, two patients (1.9%) developed new soft-tissue disease; one developed right iliac fossa lymphadenopathy after 8 months and the other developed a perirectal mass after 12 months. The patient with new lymphadenopathy also had multiple new bone lesions identified by bone scan and PSA progression. The patient with the perirectal mass had PSA progression and a palpable abnormality. CONCLUSION: This review of patients with AIPC and bone metastasis only, followed for a median of 8 months on clinical trials, shows that the incidence of asymptomatic new soft-tissue disease as the only sign of disease progression is quite low. Therefore, routine CT to exclude new soft-tissue disease in this population appears to be unwarranted. We recommend that for these patients CT is done only at the time of disease progression, as shown by bone scan, PSA level, or clinical presentation. We do not exclude the possibility that patients who remain on trial for significantly longer periods might benefit from routine interval CT.     

Prognostic and predictive factors in patients with androgen-independent prostate cancer treated with docetaxel and estramustine: a single institution experience

OBJECTIVES: To investigate potential prognostic and predictive factors in patients with androgen-independent prostate cancer (AIPC) treated with docetaxel chemotherapy. METHODS: This analysis included 94 consecutive AIPC patients who were treated between March 2001 and May 2006 with biweekly docetaxel 45 mg/m(2) (day 2) and estramustine 140 mg three dimes daily (days 1-3). RESULTS: Prostate-specific antigen (PSA) responses were observed in 45 of 84 evaluable patients (53%), whereas objective responses were observed in 16 of 40 patients with measurable disease (40%). Median survival (OS) was 16.2 mo (95% confidence interval [CI], 12.9-19.4) and median time to PSA progression (TTP) 5.0 mo (95%CI, 3.6-7.1). OS was independently associated with pain score baseline PSA and weight loss. Patients with only extraosseous disease had higher PSA response rate (87% vs. 49%, p=0.014) and superior TTP compared with patients with bone metastases with or without extraosseous disease (7.3 vs. 4.3 vs. 4 mo, p=0.002). Concurrent bone and extraosseous metastases were associated with worse prognosis compared with each site alone (median OS: 12.3 vs.19 vs.18.3 mo, p=0.007). CONCLUSIONS: Among patients with AIPC treated with biweekly docetaxel and estramustine, baseline PSA >100, existence of pain, weight loss, and simultaneous extraosseous and bone disease were associated with worse prognosis. Extraosseous metastases seem to be more sensitive than bone disease to this chemotherapy.     

Prostate-specific antigen flare phenomenon with docetaxel-based chemotherapy in patients with androgen-independent prostate cancer

OBJECTIVE

To evaluate the prostate‐specific antigen (PSA) ‘flare’ phenomenon in patients with androgen‐independent prostate cancer (AIPC) treated with docetaxel, as flare is a known effect of androgen‐deprivation therapy in hormone‐dependent prostate cancer.

PATIENTS AND METHODS

The charts of 56 patients who received docetaxel‐based chemotherapy in three different centres from August 1999 to August 2007 were reviewed retrospectively. The biochemical response was characterized according to the Bubley criteria. There was an immediate PSA response (PSA decline ≥ 50%) in 23 (41%) patients, PSA stabilization (PSA decline < 50%) in 16 (29%) and PSA progression in nine (16%). There was also a fourth response, i.e. PSA flare, defined as an increase in PSA level with no symptomatic progression, after starting docetaxel‐based chemotherapy administered every 3 weeks.

RESULTS

Eight (14%) patients with PSA flare were identified; all had osseous disease and five had additional soft‐tissue disease. The PSA flare lasted a median (range) of 21 (21–42) days and it spread over a median of 1 (1–2) cycles. The temporary PSA surge exceeded baseline values by a median (range) of 61.5 (12–404)%. There was a subsequent PSA response in six of the eight patients and PSA stabilized in the remaining two. Patients with flare received a median of 8.5 (5–12) treatment cycles, vs a median of 8 (2–12) in the immediate PSA response group (P = 0.103, Student’s t‐test). The Response Evaluation Criteria in Solid Tumors criteria evaluation showed one patient with a partial response and six with stable disease. The median survival of patients with PSA flare was 12.5 months, while that of the immediate PSA responders was 20.1 months (not statistically significant, P = 0.168, log‐rank test).

CONCLUSION

Of patients with AIPC, 14% had an initial PSA flare after starting docetaxel‐based chemotherapy. The occurrence of PSA flare had no effect on treatment duration or outcome. With lack of clinical progression, docetaxel‐based chemotherapy should be administered for at least two 3‐week cycles before further decisions are made about efficacy.     

Optimal timing of chemotherapy in androgen independent prostate cancer

PurposeTo interpret available docetaxel clinical trial data in order to define optimal timing of the initiation of chemotherapy in androgen independent prostate cancer (AIPC).Materials and methodsPublished literature on the natural history of nonmetastatic AIPC was reviewed. Phase III clinical trials using docetaxel-based therapy were analyzed as well as their associated quality of life (QOL) findings. Trials using docetaxel in earlier stage of the disease, as well those using novel agents were examined.ResultsBased on one report, non-metastatic AIPC is relatively indolent, and there is currently no evidence that supports the use of chemotherapy in this disease subset. The results of TAX 327 and SWOG 9916 demonstrate that chemotherapy is indicated for metastatic AIPC. However, based on available data, more than one hormonal maneuver can be offered to patients before chemotherapy is initiated. Timing of docetaxel therapy can further be individualized based on risk, clinical status, and patients' values and preferences. Building on the success of docetaxel, several novel agents that target different pathways are being tested in combination with, or as an alternative to, docetaxel-based therapy in Phase III clinical trials.ConclusionsCurrently, docetaxel therapy should be reserved for patients with metastatic AIPC who have progressed despite one or more hormonal therapies. In most patients, more than one hormonal treatment can be offered before chemotherapy is initiated. Studies that test the efficacy of chemotherapy early in the natural history of prostate cancer are under way or are planned.     

The efficacy of abiraterone acetate in treating Taiwanese chemo-refractory metastatic castration-resistant prostate cancer patients

ObjectiveTo evaluate the efficacy of abiraterone acetate in combination with prednisolone in Taiwanese men with metastatic castrate-resistant prostate cancer (mCRPC) who failed docetaxel-based chemotherapy.Materials and methodsIn this single-arm, open label study, 30 mCRPC patients with prostate specific antigen (PSA) progression after docetaxel chemotherapy were enrolled. All patients were treated with abiraterone acetate 1000 mg once daily and prednisolone 5 mg twice daily. The primary end-point was PSA response rate (defined as proportion of patients achieving a PSA decline of ≥50%). Secondary end-points were overall survival and time-to-PSA progression.ResultsAmong 28 patients who received one or more cycles of treatment, 15 (53.6%) men achieved PSA response [95% confidence interval (CI) 33.9–72.5]. The median time-to-PSA progression was 5.5 months (95% CI 3.1–7.9). The median interval from stopping abiraterone to death was 3.4 months (95% CI 0.1–21.0), and the median overall survival was 19.2 months (95% CI 13.0–25.4). The PSA responders had better overall survival compared with PSA nonresponders, in both univariate (log rank test, p = 0.007) and multivariate (Cox regression, p = 0.001; relative risk: 0.31; 95% CI: 0.12–0.76) analysis. Both a high Gleason score (≥8) and viscera involvement did not have an unfavorable response to abiraterone treatment.ConclusionA combination of abiraterone acetate and prednisolone can improve the overall survival in Taiwanese mCRPC patients who fail prior docetaxel chemotherapy.     

Significance of docetaxel-based chemotherapy as treatment for metastatic castration-resistant prostate cancer in Japanese men over 75?years old

Objectives

The objective of this study was to evaluate the significance of docetaxel-based chemotherapy in elderly Japanese men with metastatic castration-resistant prostate cancer (CRPC).

Materials and methods

This study included a total of 159 consecutive patients aged ??75?years with mCRPC who were treated with docetaxel-based chemotherapy. The efficacy and tolerability of this therapy were retrospectively analyzed.

Results

In these 159 patients, the median age and prostate-specific antigen (PSA) level before docetaxel-based chemotherapy were 78?years and 44.0?ng/ml, respectively. Of these patients, 42 (26.4?%) and 117 (73.6?%) received docetaxel as a weekly (30?mg/m²) and 3-weekly (70?mg/m²) regimen, respectively, and estramustine was administered combining with docetaxel in 77 (48.4?%). Following docetaxel-based chemotherapy, PSA declined in 118 patients (74.3?%), including 87 (54.6?%) achieving a PSA decline ??50?%, and the median progression-free survival and overall survival (OS) were 2.9 and 23.2?months, respectively. Of several factors examined, univariate analysis identified performance status (PS), significant clinical pain, bone metastasis, schedule of treatment, treatment cycle, and PSA response as significant predictors of OS, of which only PS, treatment cycle, and PSA response appeared to be independently associated with OS on multivariate analysis. The major grade 3?C4 toxicities were myelosuppression, including neutropenia, anemia, and thrombocytopenia in 78 (49.1?%), 22 (13.8?%), and 14 (8.8?%), respectively.

Conclusions

These findings suggest that docetaxel-based chemotherapy is clinically feasible in Japanese men aged ??75?years with mCRPC considering the cancer control as well as safety associated with this therapy.     

Chemotherapy in hormone-refractory prostate cancer

The results of the TAX 327 and SWOG 99-16 trials for the first time showed an improvement in overall survival (OS) with docetaxel-based chemotherapy in patients with metastatic hormone-refractory prostate cancer. As such, 3-weekly (q3w) docetaxel plus low-dose prednisone is widely considered to be the treatment of choice for these patients. An updated survival analysis from TAX 327 confirms that benefits observed with docetaxel are sustained at 3 years. Furthermore, q3w docetaxel plus prednisone was effective in all patient subgroups investigated, regardless of age, presence or absence of pain, and performance status. Multivariate analysis has shown that prostate-specific antigen (PSA) concentrations and kinetics (pre-treatment PSA doubling time; PSADT) are independent prognostic factors for survival in the TAX 327 cohort, along with pain, number of metastatic sites and measurable disease. Patients with baseline PSA concentrations of <114 ng/mL and PSADT > or =55 days have a median overall survival of 25 months while those with PSA concentrations of > or =114 ng/mL and a PSADT of <55 days have a median overall survival of only 14 months. A PSA decline of > or 1=30% within 3 months' therapy with docetaxel is also a surrogate of OS. Measurements such as these, and the use of predictive nomograms, can assist the physician in identifying patients at high risk of disease progression who may benefit from earlier treatment with chemotherapy.     

Oncological outcome of docetaxel-based chemotherapy for Japanese men with metastatic castration-resistant prostate cancer

ObjectivesTo retrospectively review the oncologic outcomes of docetaxel-based chemotherapy in Japanese men with metastatic castration-resistant prostate cancer (mCRPC).Materials and methodsThis study included 257 consecutive Japanese patients with mCRPC who were treated with docetaxel-based chemotherapy between April 2007 and March 2010. The prognostic significance of several clinicopathologic factors in these patients was analyzed.ResultsIn these 257 patients, the median age and serum value of prostate-specific antigen (PSA) prior to docetaxel-based chemotherapy were 72 years and 43.0 ng/ml, respectively. Of these patients, 64 (24.9%) and 193 (75.1%) received docetaxel as a weekly (30 mg/m²) and 3-weekly (70–75 mg/m²) regimen, respectively, and estramustine (EM) was administered in combination with docetaxel in 137 (53.3%). PSA decline was observed in 205 patients (79.8%), including 143 (55.6%) achieving PSA decline ≥ 50%. The median progression-free survival and overall survival (OS) were 4.3 and 25.4 months, respectively. Of several factors examined, univariate analysis identified performance status (PS), PSA value, significant clinical pain, bone metastasis, prior treatment with EM, treatment cycle, and PSA response as significant predictors of OS, of which only PS, significant clinical pain, prior treatment with EM, treatment cycle, and PSA response appeared to be independently related to OS on multivariate analysis. Furthermore, there were significant differences in OS according to positive numbers of these 5 independent risk factors.ConclusionsOncologic outcomes in Japanese mCRPC patients receiving docetaxel-based chemotherapy is generally favorable, and the risk stratification presented in this study may contribute to precisely predicting the prognosis of such patients.     

PSA doubling time in prostate cancer relapsed after endocrine therapy

PURPOSE: The PSA level of prostate cancer patients generally declines after endocrine therapy, but elevates when the cancer relapses in most cases. However, the rate of elevation differs with the case. We investigated the PSA doubling time (PSA-DT) of the prostate cancer patients whose PSA declined after endocrine therapy and later re-elevated, and investigated the relationship with other parameters. PATIENTS AND METHODS: We investigated 55 prostate cancer patients who underwent endocrine therapy between 1991 and 1998. Their PSA re-elevated continuously after their PSA fell below 10 ng/ml after the endocrine therapy as the first line treatment. First, the correlation coefficients with time and PSA were calculated in order to decide whether their PSA elevation was exponential or linear. PSA-DT was calculated thereafter, and compared with the clinical stage, pathological differentiation, clinical relapse style, time from the beginning of the therapy to PSA relapse, pre-treatment PSA value, and prognosis. The relationship between PSA-DT and each clinical parameter was tested using the Kruskal-Wallis test. Differences in survival rates and PSA-DT were calculated using the log-rank test. RESULTS: PSA elevated exponentially after cancer relapsed. PSA-DT in all cases ranged from 0.5 to 26.3 months, with an average of 4.4 +/- 4.8 (S.D.) months and the median was 2.5 months. PSA-DT was significantly (p < 0.01) short when the pre-treatment clinical stage was high, the time from the beginning of the therapy to PSA relapse was short, or the pre-treatment PSA value was high. PSA-DT tended to be short when the pre-treatment pathological differentiation was low, but not significantly. PSA-DT tended to be short when the cancer relapsed as distant metastasis rather than regional relapse, but not significantly. Prognosis from the initial treatment and PSA relapse was significantly poor when the PSA-DT was short. CONCLUSIONS: PSA elevated exponentially in the relapsed prostate cancer patients after the endocrine therapy. PSA-DT was distributed in a very wide range, and this value was considered to reflect the malignant potential and prognosis of the cancer. PSA-DT may be useful for determining the strategy after relapse.     

Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer

Objectives

Docetaxel is considered first-line chemotherapy for patients with metastatic castrate resistant prostate cancer (CRPC). Carboplatin and paclitaxel have demonstrated activity in CRPC but published data are limited regarding use after docetaxel.

Methods

A retrospective, bi-institutional review was conducted of patients with advanced CRPC treated with carboplatin plus paclitaxel after docetaxel. Therapy was evaluated for tolerability, response, and survival. Endpoints used modified Prostate Cancer Working Group 2 criteria.

Results

Twenty-five patients were identified from February 2000 to March 2008. Median pretreatment PSA was 130.2 ng/ml [range 0.1–2100]. Sites of metastases included bone (88%), lymph nodes (52%), pelvis (32%), lung (28%), and liver (20%). A median 4.5 cycles of docetaxel [range 1–22] were given with a median progression-free survival (PFS) of 12 weeks [range 2–68]. Eighty-eight percent of patients (22/25) were docetaxel-refractory at the initiation of therapy with carboplatin (AUC 4–6) day 1 plus paclitaxel 60–80 mg/m² days 1, 8, and 21 recycled every 28 days. Patients received a median of 3.5 cycles [range 1–8] of carboplatin/paclitaxel with a median PFS of 12 weeks [range 2–35]. Sixty-four percent of patients (16/25) achieved ≥30% reduction in PSA with a median overall survival of 42 weeks [95% CI 30.6–53.5 weeks]. Grade 3 or 4 adverse hematologic events occurred in 11/25 (44%) patients, with no neutropenic fever or grade 3/4 non-hematologic toxicity.

Conclusion

Carboplatin/paclitaxel chemotherapy following docetaxel in metastatic CRPC is well tolerated with favorable PSA response rates and survival. This combination is a viable option after progression on docetaxel-based therapy.     

The pattern of serum markers in patients with androgen-independent adenocarcinoma of the prostate

In this exploratory study, our objectives were to correlate the serum and bone marrow concentrations of putative markers of prostate cancer progression in patients with advanced androgen-independent prostate cancer (AIPC), to assess the frequency and quantity of relative expression of these markers, and to correlate the expression of the markers with extent of disease (EOD) and overall survival. In a cohort of 50 patients with AIPC with bone metastases, we obtained serum and bone marrow samples and measured prostate specific antigen (PSA), serum interleukin-6 (sIL-6), bone marrow interleukin-6, serum chromogranin A (sCgA), bone marrow chromogranin A, and prostate specific membrane antigen (PSMA) by immunoassays. EOD was determined by quantifying identifiable bone lesions on radionuclide bone scans. Each variable was categorized into two groups (low and high) based on the median found in this cohort or on the cutoff based on normal limits when available. Analyses were performed in two subsets of patients with EOD either <20 or >/=20. Results showed that: (1) PSA is associated with EOD but not with outcome; (2) sIL-6 and sCgA may be intermediate markers of early progression in AIPC, because they are predictive of outcome only in patients with EOD <20; (3) elevated PSMA is associated with elevated sIL-6 but not with PSA, suggesting that PSMA may be a useful marker in AIPC; and (4) the ratio of PSA to putative markers of progression may reflect the complex clonal progression of prostate cancer. We conclude that patients with advanced AIPC exhibit one of two patterns of serologic marker expression: in some patients the disease status is reflected by PSA, and in others it is reflected by other markers. If these data are prospectively confirmed, this would help group patients with advanced AIPC into clinically relevant categories.     

Prostate-specific antigen in patients with relapsed prostate cancer following endocrine treatment

We assessed the relationship between changes in PSA and prognosis, as a possible reflection of tumour growth in patients who relapse following primary endocrine therapy. In 8 patients in whom no therapeutic change was attempted after PSA relapse, the PSA level increased exponentially. Their PSA-DT had a close positive relation-ship to the duration of survival after relapse (r=0.79, p=0.02). In 6 patients who received chemotherapy after relapse, PSA-DT between PSA relapse and initiation of chemotherapy also had a relationship to the duration of survival after relapse (r=0.87, p=0.05). It appears to be reasonable to conclude from these findings that the PSA-DT value is regarded to be a factor associated with prognosis in cases with an exponential increase in PSA after relapse.     

Deferred combined androgen blockade therapy using bicalutamide in patients with hormone-refractory prostate cancer during androgen deprivation monotherapy

OBJECTIVE: To assess the effect of adding bicalutamide on serum prostate-specific antigen (PSA) levels in patients with hormone-refractory prostate cancer (HRPC) during androgen deprivation monotherapy (ADMT). PATIENTS AND METHODS: Forty-four patients with HRPC were treated with deferred combined androgen blockade (CAB) therapy, administering bicalutamide 80 mg once daily. HRPC was defined biochemically as three consecutive rises in PSA level during ADMT. The treatment response was defined as a > or = 50% decline in PSA levels. Prognostic values of various pretreatment variables for responsiveness to deferred CAB were determined statistically. When the disease relapsed during deferred CAB, bicalutamide was discontinued and the patients were evaluated for the antiandrogen withdrawal syndrome (AWS). RESULTS: Of the 44 patients, 29 (66%) had a PSA response; the median PSA failure-free survival was 9.2+ months. Biopsy Gleason score was the only pretreatment variable predictive of a PSA response (mean Gleason score 7.9 in responders and 8.7 in nonresponders). The PSA doubling time (PSA-DT) was the only statistically significant variable of PSA failure-free survival in a multivariate analysis. The 1- and 2-year PSA failure-free survival rates were 43% and 31% in patients with a PSA-DT of >4 months, while it was 21% and none, respectively, in those with a PSA-DT of <4 months. Responders to deferred CAB had a statistically longer cancer-specific survival than nonresponders. None of 20 patients who were evaluated for AWS had the condition. CONCLUSIONS: Deferred CAB therapy using bicalutamide is effective in patients with progression during ADMT, particularly in those with lower Gleason score tumours or a longer PSA-DT. AWS after deferred CAB is uncommon.     

Role of Chemotherapy in Nonmetastatic Hormone-Refractory Prostate Cancer

ContextDocetaxel chemotherapy has become the standard first-line treatment for metastatic hormone-refractory prostate cancer (HRPC). Nowadays, one of the goals of research is to determine optimal management strategies for different patient populations with prostate cancer.ObjectiveBecause the utility of docetaxel in patients with nonmetastatic HRPC has not yet been evaluated, one of the most challenging questions is to define the role of chemotherapy in nonmetastatic HRPC.Evidence acquisitionIn a recently published subset analysis of TAX-327, a multivariate prognostic model incorporating prostate-specific antigen (PSA) kinetics has been developed to predict survival at 1, 2, and 5 yr in men with metastatic HRPC treated with chemotherapy. This novel model includes PSA doubling time (PSA DT), baseline pain, baseline PSA level, age, type of progression at baseline (measurable disease or bone scan compared with PSA only), presence of liver metastases, and the number of metastatic disease sites.Evidence synthesisThe authors found a statistically significantly better overall survival in patients with PSA ≤114 ng/ml and PSA DT >55 d. Patients with a PSA DT of <55 d had a worse prognosis than patients with a longer PSA DT.ConclusionsBased on these findings, it seems clear nowadays that evaluation of PSA kinetics can help us to delineate the potential benefits of the early indication of chemotherapy. It could be hypothesized that docetaxel-based chemotherapy could have a role in those patients with nonmetastatic HRPC who have a very short PSA DT.     

Quimioterapia sistémica basada en docetaxel en hombres coreanos mayores con cáncer de próstata resistente a la castración

IntroductionThe aim of this study was to determine the efficacy and safety of docetaxel-based systemic chemotherapy in elderly patients with castration-resistant prostate cancer (CRPC).Material and methodsWe retrospectively reviewed the clinical records of 36 patients with CRPC who were treated with docetaxel-based systemic chemotherapy at a single institution between May 2005 and April 2010. After screening, 30 patients met the eligibility criteria, and were included. Patients were placed into 2 groups: group 1 consisted of 9 patients aged <70 years, and group 2 consisted of 21 patients aged ≥70 years. The treatment consisted of prednisolone (5 mg) twice daily and docetaxel (75 mg/m²) once every 3 weeks.ResultsThe median age was 72 years, and the median performance status was 0. The median baseline prostate specific antigen (PSA) was 33.8 ng/mL. The mean number of docetaxel chemotherapy cycles was 5.8. The PSA response rate was 48.2%, and the measurable disease response rate was 15.0%, and these rates did not differ between the two groups. The median time to PSA progression and median overall survival were 6 and 9 months, respectively. Five patients experienced grade 3 or higher neutropenia. The drug-related toxicity was not different between the two groups.ConclusionsThe response of elderly CRPC patients with good performance status to docetaxel-based systemic chemotherapy was similar to that of younger patients. Docetaxel-based systemic chemotherapy is generally tolerated in elderly patients with good performance status.     

Serial spot hydroxyproline/creatinine ratios in metastatic prostatic cancer

Analysis of urinary hydroxyproline levels offers a marker to monitor osseous involvement in patients with metastatic malignancies. Such a marker is needed in patients with prostatic cancer when bone metastases predominate. Thirty-two men with stage D2 prostatic cancer were monitored by bone scan, acid and alkaline phosphatase values, and urinary hydroxyproline, beginning from 4 to 36 months after initiation of hormonal manipulation and/or systemic chemotherapy. In patients with disease progression determined by bone scan serial urinary hydroxyproline values progressively increased and were significantly elevated compared to urinary values obtained from patients with a stable or improving scan (p less than 0.001). Simultaneous alkaline phosphatase determinations showed less significant differences between patient groups. Acid phosphatase did not reliably indicate osseous response to therapy. These data suggest that urinary hydroxyproline values are predictive as an early objective sign of osseous response in patients receiving therapy for stage D2 prostatic cancer.     

Magnetic resonance imaging of the axial skeleton enables objective measurement of tumor response on prostate cancer bone metastases

BACKGROUND: There is currently no technique to image quantitatively bone metastases. Here, we assessed the value of MRI of the axial skeleton (AS-MRI) as a single step technique to quantify bone metastases and measure tumor response. METHODS: AS-MRI was performed in 38 patients before receiving chemotherapy for metastatic HRPCa, in addition to PSA, computed tomography of the thorax, abdomen, and pelvis [CT-TAP]; and Tc-99m bone scintigraphy. A second AS-MRI was performed in 20 patients who completed 6 months of chemotherapy. Evaluation of tumor response was performed using RECIST. RESULTS: Only 11 patients (29%) had RECIST measurable metastases in soft-tissues or lymph nodes on baseline CT-TAP. AS-MRI identified a diffuse infiltration of the bone marrow in 8 patients and focal measurable metastatic lesions in 25 patients (65%), therefore, doubling the proportion of patients with measurable lesions. Transposing RECIST on AS-MRI in 20 patients who completed 6 months of treatment, allows the accurate estimation of complete response (n = 2), partial response (n = 2), stable disease (n = 5), or tumor progression (n = 11), as it is done using CT-TAP in soft tissue solid metastases. CONCLUSIONS: MRI of axial skeleton enables precise measurement and follow-up of bone metastases as it is for other soft-tissue metastasis.     

PSA-related parameters in prostate cancer relapsed after endocrine therapy

PURPOSE: Prostate cancer is generally controlled by endocrine therapy even in an advanced state, but relapse may occur in many cases. Generally, the prognosis of a relapsed case is poor, but the prognosis differs case by case. We experienced 74 cases of prostate cancer relapsed after effective endocrine therapy, and investigated the relationship between the PSA-related parameters, clinical stage and prognosis. PATIENTS AND METHODS: We investigated 74 prostate cancer patients whose PSA declined 10 ng/ml or lower by the treatment consisting of endocrine therapy, but relapsed later. Pre-treatment PSA, the value of PSA nadir, the period from the start of treatment to PSA nadir, the period from the start of treatment to relapse, PSA doubling time (PSA-DT) at relapse and PSA response to the second line therapy at relapse were calculated, and compared with the clinical stage and prognosis. The relationship between each PSA parameter and clinical stage was tested using the Kruskal-Wallis test and chi 2 test. Cancer-specific survival after relapse in stage D patients was calculated by the Kaplan-Meier method and differences in prognosis were tested using the Logrank test. RESULTS: Pre-treatment PSA was significantly (p < 0.01) high, while the period from the start of treatment to relapse (p < 0.05) and PSA-DT at relapse (p < 0.01) was significantly short as the stage progressed. According to PSA response to the second line therapy at relapse, the rate of CR + PR was significantly (p < 0.05) high in clinical stage B + C group compared to clinical stage D group. The prognosis after relapse was significantly poorer in patients with relapse within 10 months after start of treatment than in those with relapse later, and in patients whose PSA-DT at relapse was shorter than 2 months than in those with a longer PSA-DT. CONCLUSIONS: The period from the start of treatment to relapse, and PSA-DT at relapse were useful PSA-related parameters for predicting prognosis after relapse, and for determining the strategy of cancer therapy after relapse. Using these data, the physician can inform the family and the patient of the prognosis more accurately, so that they can adjust future plans.     

Impact of PSA flare-up in patients with hormone-refractory prostate cancer undergoing chemotherapy

Objectives The intention of this study is to describe the impact and underlying potential basis of the prostate-specific antigen (PSA) flare-up phenomenon in patients with hormone-refractory prostate cancer (HRPC) treated with docetaxel-based chemotherapy. Methods We retrospectively identified 74 consecutive patients who received docetaxel/estramustine-based chemotherapy at our institution. Patients were evaluated based on modified criteria from the Prostate-Specific Antigen Working Group regarding survival and toxicity. Additionally, two androgen receptor mutations derived from patients with advanced disease were analyzed for promiscuous transactivation activity. Results The 74 patients were stratified into four groups: response, partial response, flare-up-initial PSA elevation, and progression. Median survival in the flare-up group (n = 8) was 20 months and did not differ from the response group (p = 0.564). The flare-up group showed a maximum PSA elevation from baseline between 3.4 and 28.3% (between three and six weeks) followed by PSA decline ≥50% from the baseline level in seven of the eight patients. The androgen receptor mutations AR⁸⁷⁷ and AR⁷¹⁵ displayed a 37.5- and 5.2-fold increase in transactivation activity by progesterone and a 12.6- and 5.4-fold increase by estrogen compared to the AR^WT, respectively. Conclusions A considerable portion of HRPC patients experience an initial PSA flare-up under systemic chemotherapy. In this study, occurence of flare-up phenomenon did not impact survival. Chemotherapy should be continued a minimum of six weeks before removing patients from a docetaxel-based regimen. We showed evidence that co-medication with dexamethasone/prednisolone and/or estramustine itself can induce an initial PSA flare-up via androgen receptor mutations.     

Docetaxel reintroduction in patients with metastatic castration‐resistant docetaxel‐sensitive prostate cancer: a retrospective multicentre study

OBJECTIVE

To investigate the potential benefit of reintroducing docetaxel chemotherapy in patients with progressive metastatic castration‐resistant prostate cancer (mCRPC) who had initially responded to first‐line docetaxel‐based regimen.

PATIENTS AND METHODS

Records were evaluated retrospectively from French patients with mCRPC who had been included in seven controlled clinical studies of docetaxel as first‐line treatment. We identified patients who were confirmed as responders to first‐line treatment, discontinued for reasons other than disease progression or unacceptable toxicity, and who received further docetaxel chemotherapy for disease progression. The primary objective was to assess efficacy in terms of the prostate‐specific antigen (PSA) response after resuming a docetaxel‐based chemotherapy. Secondary objectives were overall survival and tolerance.

RESULTS

Of the 148 patients who responded to first‐line docetaxel, 50 received further therapy with docetaxel and were analysed. The median (range) response duration to first‐line docetaxel was 10.3 (4.6–45.7) months and the median docetaxel‐free interval was 18.4 (5.0–46.7) months. Docetaxel was reintroduced as second‐line therapy in 52% of patients and as further lines in 48%. After docetaxel reintroduction, 24 patients (48%) had a 50% decrease in PSA level (95% confidence interval, CI, 34.1–61.8%). The median (95% CI) overall survival from docetaxel reintroduction was 16 (13–20) months. Re‐treatment was well tolerated (6% of grade 3–4 haemotoxicity).

CONCLUSION

Docetaxel reintroduction appears to be effective, with favourable tolerance profiles, in patients with mCRPC having responded to first‐line docetaxel, and should be prospectively assessed in clinical trials against alternative therapies or investigational agents given alone or in combination, to define further management.