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Journal of Clinical Oncology, Vol 20, Issue 14 (July), 2002: 3072-3080
© 2002 American Society for Clinical Oncology

Results of a Phase II Study With Doxorubicin, Etoposide, and Cisplatin in Patients With Fully Characterized Small-Cell Carcinoma of the Prostate

By Christos N. Papandreou, Danai D. Daliani, Peter F. Thall, Shi-Ming Tu, Xuemei Wang, Adriana Reyes, Patricia Troncoso, Christopher J. Logothetis

From the Departments of Genitourinary Medical Oncology, Biostatistics, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030.

Address reprint requests to Christos N. Papandreou, MD, PhD, The University of Texas M.D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, 1515 Holcombe Blvd, Box 427, Houston, TX 77030; email: cpapandr{at}notes.mdacc.tmc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To determine the activity and toxicity of doxorubicin in combination with cisplatin and etoposide in patients with small-cell prostate carcinoma (SCPCa) and to characterize the clinicopathologic features of SCPCa.

PATIENTS AND METHODS: Patients with SCPCa (pure or mixed), measurable disease, good organ function, and no prior treatment with doxorubicin, etoposide, or cisplatin were treated every 4 weeks with doxorubicin 50 mg/m2 as a 24-hour intravenous (IV) infusion followed by etoposide 120 mg/m2/d and cisplatin 25 mg/m2/d IV on days 2 to 4.

RESULTS: Thirty-eight patients (36 assessable for response) were treated for a median of four cycles. Twenty-nine (81%) of 36 patients had prior hormonal therapy. Study patients had visceral metastases, lytic bone disease, and relatively low serum prostate-specific antigen (PSA). We observed 22 partial responses (response rate, 61% in an intent-to-treat analysis); toxicity was severe (grade 3 or 4 neutropenia 100%, thrombocytopenia 66%, mucositis 21%, and infection 68%). Three patients died of toxicity. Median time to progression and overall survival time were 5.8 months and 10.5 months, respectively. Performance status, serum albumin, and number of organs involved (but not PSA, carcinoembryonic antigen, or neuroendocrine markers) were predictors of survival.

CONCLUSION: SCPCa presents unique clinicopathologic features. Addition of doxorubicin to the etoposide/cisplatin regimen caused higher toxicity in this patient population and failed to improve outcome. Given these results, we do not recommend further development of this regimen for patients with SCPCa. Improvement in therapy will come from understanding the biology of SCPCa progression and integrating new targeted therapies into the treatment of SCPCa.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
SEVERAL REPORTS OVER the past decade described the clinical and pathologic features of small-cell carcinoma of the prostate (SCPCa)1-4 that differ from those of acinar adenocarcinoma. These features include frequent visceral metastases, lytic bone involvement, relative low serum prostate-specific antigen (PSA) concentration, resistance to androgen ablation, and a high response rate to etoposide/cisplatin chemotherapy.1-3

The histogenesis of SCPCa is still controversial. At least three competing theories have been proposed over the years. Initially, it was postulated that SCPCa is derived from the neural crest line/amine precursor uptake and decarboxylase (APUD) cell system,5 now called neuroendocrine system, but this was not confirmed by embryologic studies, which indicated an endodermal origin.6 In addition, neuroendocrine cells in the normal prostatic epithelium represent postmitotic cells,7 and it is unlikely, therefore, that these cells represent the ancestors of SCPCa.

On the basis of the observation that SCPCa coexists sometimes with adenocarcinoma, it was postulated that SCPCa is the product of a final dedifferentiation of the typical adenocarcinoma according to the model of divergent differentiation.3,8,9 The presence of PSA positivity in neuroendocrine cells was viewed as supporting evidence for the prostatic epithelial origin of these cells in dedifferentiated adenocarcinomas but not in SCPCa,10 given the postmitotic nature of neuroendocrine cells.

Finally, a recent third theory postulates a direct stem-cell origin for SCPCa based on the lack of immunohistologic characteristics typical of the usual prostatic epithelial cell (PSA expression and androgen receptor positivity) and the extremely high MIB-1 labeling index.11,12

Given the distinct pathologic and clinical features, investigators13-16 have excluded patients with pure or mixed SCPCa from chemotherapy trials for androgen-independent PCa. Such patients have been treated with regimens for small-cell carcinoma of the lung with some success,1,2 although the duration of response was very short.

The therapeutic implications of detecting small-cell carcinoma of the prostate have led us to a policy of frequently sampling accessible metastatic sites if the clinical features are characteristic of SCPCa. We assumed that such an approach would improve patient outcome as a consequence of the prompt application of small-cell-carcinoma–specific therapy after detection of a small-cell carcinoma component. In this trial, we wished to expand on this observation by fully characterizing our cases of SCPCa and routinely applying chemotherapy consisting of doxorubicin, etoposide, and cisplatin in combination. We hoped that this combination would improve the response rate in these complex cancers, frequently containing both acinar and small-cell carcinoma elements, over what has been seen with etoposide and cisplatin alone. Ideally, this improved efficacy would be reflected in complete remissions.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Eligibility and Evaluation
Patients with histologically proven SCPCa, either pure or in combination with adenocarcinoma, not curable by surgery or radiation therapy, and bidimensionally measurable disease were considered for this trial. Patients were required to have a life expectancy of at least 12 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3, an absolute neutrophil count (ANC) >= 1,500/µL, a platelet count >= 100,000/µL, AST and ALT levels <= four times the institutional upper limits of normal (UNL), serum total bilirubin level <= 2.0 mg/dL, calculated creatinine clearance >= 40 mL/min, and a left-ventricular ejection fraction of 55% or more. Patients with androgen ablation therapy were eligible if their serum testosterone level was less than 50 ng/dL. Prior chemotherapy was allowed if it did not include doxorubicin, etoposide, or cisplatin. At least 3 weeks had to have elapsed from any prior treatment (surgery, radiation therapy, immunotherapy, or chemotherapy), and patients should have recovered from acute toxic effects of prior therapy. Patients with brain metastases were eligible, provided that the brain disease was controlled by radiation therapy and other measurable disease existed. Patients with serious intercurrent medical illness were excluded from the trial. All patients signed an informed consent form approved by the institutional review board of The University of Texas M.D. Anderson Cancer Center before participating in the trial.

The pretreatment evaluation included a complete history and physical examination with performance status. Laboratory studies included an automated blood and platelet count (CBC), coagulation profile, serum electrolytes including magnesium level, a comprehensive screening profile (alkaline phosphatase, lactate dehydrogenase [LDH], AST, ALT, blood urea nitrogen, creatinine, calcium, phosphorus, uric acid, total protein, albumin, and total bilirubin levels), urinalysis, predicted creatinine clearance calculated by the formula of Cockcroft and Gault, carcinoembryonic antigen (CEA), PSA, prostate acid phosphatase (PAP), somatostatin, adrenal corticotrophin hormone (ACTH), antidiuretic hormone (ADH), calcitonin, bombesin, and testosterone serum levels. Other baseline studies included an ECG, ejection fraction (calculated either by a nuclear ventriculogram [MUGA] or a two-dimensional echocardiogram), chest x-ray, computed tomography (CT) scan of the abdomen and pelvis, bone scan, skeletal survey to include the involved areas on the bone scan, bone marrow aspirate and biopsy, and CT scan or magnetic resonance imaging (MRI) of the brain.

Patients had a CBC at least once weekly. A comprehensive screening profile was performed and electrolytes, including magnesium level, PSA, CEA, LDH, and alkaline phosphatase were measured at least every course or as frequently as needed to define drug toxicity. Interim history and physical examination including performance status, weight, and calculation of predicted creatinine clearance were recorded before each course. An ECG, ejection fraction assessment, and radiographic studies including a chest x-ray, CT scan of the abdomen and pelvis, and a bone scan were performed every two courses.

Response and Toxicity Criteria
All patients enrolled were assessable for toxicity. The World Health Organization grade scale was used to grade toxicity, and the worst outcome for each patient in all cycles of chemotherapy was recorded. All patients had evidence of measurable disease by study requirement and underwent tumor response assessment every two cycles of chemotherapy by means of x-ray, CT, or MRI and standard phase II response criteria.17 A minimum of 4 weeks was required to document a response. The best response was recorded for each patient. Serum levels of PSA, CEA, alkaline phosphatase, and LDH were monitored as potential tumor markers and were considered elevated and assessable for posttherapy changes if PSA more than 4 ng/mL, CEA more than UNL, alkaline phosphatase more than UNL, and LDH more than 1.5 x UNL.

The time to progression (TTP) was defined as the time from the start of therapy until evidence of disease progression. Overall survival (OS) was defined as the time from start of therapy until death.

Treatment and Dose Modifications
Treatment consisted of doxorubicin (50mg/m2) as a 24-hour intravenous (IV) infusion on day 1 followed by etoposide (120 mg/m2/d) and cisplatin (25 mg/m2/d) IV on days 2 to 4. Cisplatin was delivered as a 3-hour IV infusion with simultaneous forced diuresis using mannitol (dextrose water 5% one quarter normal saline with 40 g of mannitol/L at 200 mL/h for 2 L/d). All patients received IV antiemetic prophylaxis with 5-hydroxytryptamine-3 receptor antagonist plus 20 mg of dexamethasone. Full doses of chemotherapy were delivered if the neutrophil and platelet counts on the day of treatment were >= 1,500/µL and >= 100,000/µL, respectively. For patients with tumor involvement of the bone marrow, an absolute granulocyte count of >= 500/µL and a platelet count of >= 50,000/µL were required before chemotherapy. Doses were reduced by 20% or 40% for grade 3 or 4 toxicity, respectively. Doxorubicin was limited to a total dose of 450 mg/m2 and was discontinued if the ejection fraction decreased below 55% or to 10% below baseline or if symptoms of congestive heart failure occurred. The use of granulocyte colony-stimulating factor was allowed if grade 4 neutropenia lasted more than 7 days, if neutropenic fever occurred, or if neutropenia of grade 2 or higher persisted for 2 or more weeks from the scheduled time of chemotherapy administration. Chemotherapy was discontinued in case of progressive disease (PD), irreversible severe toxicity, patient refusal, or patient noncompliance with protocol requirements. Patients with partially responding disease continued treatment for two cycles beyond maximum response or until PD (whichever came first). Patients with stable disease continued at the discretion of the principal investigator until the disease clearly progressed.

Statistical Methods and Study Design
The primary end points for this study were objective tumor response and toxicity. The trial was planned using a Simon18 optimal two-stage design with size 0.05 and power 0.90 to detect an improvement in response probability of 0.20, from a null rate of 0.50 to alternative 0.70. This requires a sample of 21 patients in stage I and, if 12 or more responses are observed, an additional 24 patients in stage II. The experimental treatment is declared promising if there are 27 or more responses among the 45 patients, otherwise it is not promising. Unadjusted probabilities of survival rate and progression-free survival (PFS) were estimated using the method of Kaplan and Meier.19 Unadjusted between-group comparisons of OS and PFS rates were made using the log-rank test.20 The Cox proportional hazards regression model21,22 was used to assess the ability of patient characteristics or treatments to predict survival and PFS, with goodness-of-fit assessed by the Grambsch-Therneau test, Schoenfeld residual plots, Martingale residual plots, and likelihood ratio statistics.22 All scatter plots were smoothed using the Lowess method of Cleveland,23 with predictive variables transformed as appropriate based on these plots. Multivariate Cox models were obtained by performing a backward elimination with a P value cutoff of .10, then allowing any variable previously deleted to enter the final model if its P value was less than .10. Associations between pairs of binary variables were evaluated by Fisher’s exact test. Associations between pairs of quantitative variables were assessed by their Spearman correlations. All computations were carried out in Splus using standard Splus functions and the Splus survival analysis package of Therneau.24


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
From January 1, 1992, through October 1, 1999, 38 patients were enrolled. Although the study design called for accrual of a maximum of 45 patients, the study was closed after accrual of 38 patients because of a low accrual rate and excessive treatment-related morbidity. These factors and the absence of any sustained complete remission reduced the enthusiasm for continuing the trial and led to its early closure. Thirty-six patients were assessable for response. Response in two patients could not be assessed because the diagnosis of small-cell carcinoma could not be confirmed on review.

Baseline patient characteristics, pathologic findings, and biochemical parameters are listed in Tables 1 to 3. The median age was 65 years, and the average ECOG performance status was 1. Twenty-nine (81%) of the 36 patients had prior hormonal treatment; 26 patients (72%) had androgen-independent progression of their prostate carcinoma with a median duration of response to androgen ablation of 17 months (range, 1.5 months to 9 years). After the recognition of the antiandrogen withdrawal effect,25 antiandrogens were routinely discontinued if patients were receiving combined androgen blockade therapy. None of the 13 patients who underwent antiandrogen withdrawal had a response. The majority of patients (32 of 36, 89%) had metastatic disease, but the distribution was different than that seen in typical adenocarcinoma: patients commonly had liver (50%) and lung (19%) metastases whereas bone metastases were seen in 61% of patients (nearly half of whom had lytic disease). Finally, 25 (69%) of 36 patients had disease-related symptoms (bone pain requiring opioid analgesics and urinary symptoms).


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  		Table 1. Characteristics of Patients With Small-Cell Prostate Cancer
 

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  		Table 2. Comparison of Histology by H&E at Initial Diagnosis and at Study Entry
 

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  		Table 3. Baseline Biochemical Parameters
 
Nearly one third of the patients had mixed (SCPCa and adenocarcinoma) pathology. Twenty (69%) of 29 and 20 (74%) of 27 pathologic specimens available for immunohistologic analysis stained positive for chromogranin A and synaptophysin, respectively. Adenocarcinoma preceded the diagnosis of SCPCa in 27 (75%) of the 36 patients with a median time to histologic confirmation of 20 months (range, 1.5 to 120 months) (Table 2). Only a minority (31%) of the 36 patients had an elevated pretreatment serum PSA level, whereas serum CEA and LDH levels were elevated in 53% and 39% of the patients, respectively. Neuroendocrine markers were frequently elevated in the serum of these patients (Table 3).

Response to Treatment
Thirty-six patients were assessable for response. Clinical outcomes are summarized in Table 4. A total of 146 chemotherapy cycles were delivered, with a median of four cycles per patient (range, one to eight). Eight patients were withdrawn from therapy because of serious adverse events (four patients) or progressive disease (four patients).


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  		Table 4. Clinical Outcome
 
Serum tumor marker response is depicted in Table 4. Briefly, 36% of assessable patients achieved a >= 50% decline in PSA, whereas 37%, 67%, and 43%, respectively, had normalization of previously elevated serum CEA, LDH, and alkaline phosphatase levels.

Among the 22 patients with osseous metastases, nine (41%) had lytic disease. The overall best responses as demonstrated on bone scans were improvement in six (27%) of 22 patients, stable disease in 10 (46%), and progression in six (27%). On an intent-to-treat analysis, 22 (61%; 95% CI, 43% to 77%) of 36 patients achieved partial response in measurable disease. There were no complete responses (Table 4). Organ-specific measurable disease response is shown in Table 5. Responses were equally common in patients without (four of seven) or with (18 of 29) prior hormonal therapy. All patients with measurable disease regression and/or improvement or stability of bone disease by bone scan also had a concomitant decrease in PSA, CEA, and LDH concentrations of 50% or more from baseline value.


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  		Table 5. Measurable Disease Response by Site
 
Although we did not formally study quality of life and pain in this trial, 21 (84%) of the 25 symptomatic patients had pain reduction with concomitant decrease in their daily opioid analgesic requirements. During the follow-up period, seven (19%) of the 36 patients developed symptomatic brain metastases in a median time of 6 months (range, 5 to 13 months) from the initiation of chemotherapy, despite the fact that all patients had a normal CT scan or MRI of brain at study entry and no prior history of CNS metastases.

Survival and TTP Analyses
The median TTP and OS were 5.8 months (95% CI, 4.1 to 6.9 months) and 10.5 months (95% CI, 7.5 to 14.3 months), respectively, for all 36 patients.

The following variables were assessed as potential predictive covariates in Cox model analyses of TTP and OS: age, performance status, duration of hormonal response, hemoglobin (Hb), serum albumin, pretreatment serum PSA concentration, CEA, LDH, alkaline phosphatase, serum bombesin, calcitonin, ACTH, somatostatin, number of treatment cycles given, number of organs involved, and specific site of organ involvement (bone, liver, lung, lymph node/soft tissue, or prostate).

Performance status, Hb, log of pretreatment serum PSA, log of number of organs involved, and number of treatment cycles were statistically significant predictors for TTP. In the multivariate Cox model performance status, serum albumin, and log of number of organs involved were statistically significant predictors (P < .05) of OS. Having one or two cycles of treatment was a marginally significant predictor (P < .099) of OS (Table 6).


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  		Table 6. Multivariate Cox Model for OS and PFS
 
Associations Among Covariates
A high baseline serum ACTH level was associated with the presence of liver metastases (P = .07) and subsequent development of symptomatic brain metastases (P = .04). The probability of symptomatic brain metastases was statistically significantly higher (P = .01) in patients with established liver metastases (39% v 0%). Serum LDH and CEA levels were highly positively associated with the number of organs involved, whereas serum calcitonin level was associated with the presence of bone metastases (P = .05).

Toxicity
Overall, the regimen was fairly toxic (Table 7). Dose reductions (from 20% to 60%) were required in 17 (45%) of 38 patients; in two patients (5%), doxorubicin was omitted due to decrease in ejection fraction (one patient) and cardiac ischemia (one patient). There were three deaths (8%) secondary to sepsis. Not surprisingly, the most serious toxic effect of the regimen was myelotoxicity. Grade 3 or 4 hematologic toxicity included neutropenia (in 100% of patients), thrombocytopenia (in 66%), and anemia (in 26%). Blood and platelet transfusions were required in 45% and 39% of 38 patients, respectively. Mucositis was quite common and severe, with 34% and 21% of the patients having grade 2 and 3 mucositis, respectively. We believe that the high frequency of mucositis along with the severity of myelosuppression contributed to the high rate of infections. Twenty-eight (74%) of the 38 patients required at least one hospitalization for neutropenic infection. The incidence of nausea and vomiting was typical of a cisplatin-containing regimen: 34% and 21% of the patients had grade 3 or 4 nausea and vomiting, respectively. Neuropathy was seen but was not debilitating. Renal toxicity was rare with the inpatient delivery of cisplatin in three daily divided doses and aggressive hydration and mannitol diuresis. The only episode of grade 3 renal toxicity was related to disease progression in the pelvis, causing bilateral hydronephrosis.


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  		Table 7. Adverse Events (N = 38)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
These data confirm the high response rate of the small-cell variant of prostate cancer to systemic chemotherapy. However, no patient achieved a durable complete remission, and the median TTP was very short. Given the increase in toxicity without obvious proportional therapeutic gain, we believe that the addition of doxorubicin to etoposide/cisplatin is not an improvement.

The response rate is similar to that seen in small-cell carcinoma arising in other organ sites (lung or bladder).26,27 This suggests that the presence of the small-cell phenotype takes precedence over the anatomic origin in predicting response to treatment and cancer progression.

Our patients were selected based on pathologic criteria (presence of small-cell elements). Nine (25%) of the 36 patients enrolled in the study presented at initial diagnosis with SCPCa, either pure (three of 36) or mixed with high-grade adenocarcinoma (six of 36). The remaining 27 patients had a prior diagnosis of adenocarcinoma (eight moderately differentiated and 19 poorly differentiated). There is a trend, although not statistically significant, for a longer interval from first diagnosis to the recognition of the small-cell component in patients with an initial diagnosis of moderately differentiated (42.5 months; range, 14 to 119 months) compared with those with high-grade adenocarcinoma (18 months; range, 1 to 96 months).

A repeat biopsy in the patients with preexisting adenocarcinoma was prompted by the recognition of previously described1-3 clinical features that predict for a small-cell component. One or more of these clinical features were shared by the majority (32 of 38, 84%) of our patients: a short or no response to androgen ablation before histologic transformation to SCPCa; high prevalence of lytic bone metastases; rapidly progressive disease in a seemingly stable patient; marked clinical symptomatology, usually in association with visceral metastases, large prostatic/pelvic mass, or bulky lymphadenopathy; and/or a serum PSA level disproportionately low relative to tumor volume assessed radiographically (Tables 1 and 3).

Objective response was seen in 61% of patients and included all organs involved, regardless of the hormonal status of the patients. Clinical response paralleled symptom improvement and normalization of elevated tumor-associated marker levels (PSA, CEA, alkaline phosphatase, and LDH). Although we observed a high response rate and significant palliation, the TTP was short, and the survival remained disappointedly brief. In fact, the OS did not improve over that previously reported with etoposide and cisplatin alone.2 The addition of doxorubicin added to the toxicity of the regimen, with significant myelosuppression and mucositis that contributed to a high rate of neutropenic infections and 8% mortality. The excessive toxicity observed may have been related to the combination chemotherapy, the poor reserves of some of these patients, or both. Thus, neither awareness of the SCPCa clinical phenotype nor the histologic recognition of the SC component or the addition of doxorubicin helped alter the short duration of response.

In this study, we confirmed the importance of biologic characteristics and the predictive value of identifying small-cell carcinoma. Several parameters were analyzed as predictors of response and survival time. Performance status, serum albumin level, and log of number of organs involved by metastases were predictors of survival time in multivariate analysis. Levels of serum PSA, CEA, LDH, alkaline phosphatase, and markers of neuroendocrine differentiation (bombesin, calcitonin, ACTH, and somatostatin) or chromogranin A and/or synaptophysin positivity by immunohistochemistry were not independent prognostic factors for survival.

The importance and predictive value of the small-cell component is highlighted by the fact that patients with mixed histology (adenocarcinoma and small-cell carcinoma) lived 3 months longer overall compared with patients with pure SCPCa (12.3 months v 9.16 months). Also, a higher pretreatment PSA level carried a lower relative risk and was a positive predictor for time to failure. A plausible explanation for this is that pretreatment PSA levels may reflect the percentage and the histologic maturity of the adenocarcinoma component coexisting with SCPCa, which in turn may dictate the overall biologic behavior of the hybrid tumor. Finally, none of the 13 patients who underwent antiandrogen withdrawal responded. This observation is in accordance with the fact that SCPCa and prostate cancer with neuroendocrine differentiation are deprived of androgen receptor.28-30 We, therefore, do not recommend a waiting period for antiandrogen withdrawal in patients with SCPCa before initiation of chemotherapy.

We found an intriguing statistically significant association between brain and liver metastases. Patients with liver metastases had a much higher probability (39%) of subsequent development of symptomatic brain metastases compared with those without liver metastases (0%). In addition, high serum ACTH levels were associated with higher rates of both liver metastases (P = .07) and brain metastases (P = .04), a fact that could be exploited clinically. However, because of our small sample size, these findings are only suggestive.

It is interesting to note that the precursor of ACTH (NH2-terminal portion of pro-opiomelanocortin) has been reported to correlate with the presence of liver metastases and disease recurrence in patients with small-cell lung cancer.31 We speculate that the metastatic pattern in these patients may be attributed to the presence of ligand/receptor pairs that are not randomly distributed in various anatomic sites. Specifically, SCPCa cells expressing high-affinity receptors for bombesin, calcitonin, and insulin-like growth factor (IGF)-I32-34 metastasize toward organ sites (liver and brain), which express a rich milieu of the respective ligands/growth factors (calcitonin, bombesin, and IGF-I/II).35-38 Whether acquisition of a neuroendocrine phenotype (ACTH, bombesin, calcitonin) along with a possible host-tissue specific conditioning of SCPCa cells in the liver environment enables them to increase their metastatic potential to the brain is unclear. None of the neuroendocrine markers (bombesin, calcitonin, ACTH, chromogranin A, or synaptophysin), however, was a predictor of TTP or OS.

As discussed, all patients in this study shared the clinical phenotype characteristics of SCPCa. In addition, in most patients (75%), conventional adenocarcinoma preceded or coexisted with a small-cell component, representing the occurrence of the well-described, time-related dedifferentiation of PCa.39

These data suggest that small-cell anaplastic prostate cancer represents a clinicopathologic continuum, whereby a characteristic biologic/clinical phenotype reflects the histologic continuum of the disease. This observation also raises the question of whether some patients with adenocarcinoma of the prostate (without small-cell elements) who present with similar clinical and laboratory characteristics would share a prognosis similar to that of patients with an established SCPCa diagnosis. Empirically, we have encountered patients in whom the clinical phenotype led us to perform tumor biopsies in expectation of detecting small-cell elements. However, these patients did not always have histologic features of small-cell cancer. Whether patients with the clinical phenotype without histologic evidence of small-cell cancer are responsive to etoposide/platinum-based therapy is an important question that needs to be addressed. Such investigation may be facilitated by the study of the specific histologic features that are mechanistically implicated in or correlated with neuroendocrine progression. These markers may identify a broader subset of patients with adenocarcinoma of the prostate who may develop a clinical phenotype akin to the fully developed small-cell carcinoma picture.

Most (81%) of the patients in our study were treated with androgen ablation before the emergence of the small-cell phenotype with neuroendocrine features. Whether such hormonal manipulation facilitates the transition to a more aggressive phenotype is currently unknown. However, there are preclinical data to suggest that androgen withdrawal may result in the acquisition of neuroendocrine features40 and progression to androgen independence which at least in part, could be attributed to the loss of neutral endopeptidase (CD10 and NEP)41 and the resultant decrease in the catalytic degradation of neuropeptides (bombesin, neurotensin, endothelin, and so on) known to be autocrine growth factors for androgen-independent prostate cancer.42-44 If the role of androgen withdrawal in the progression to androgen independence were to be verified at the clinical level, it would then make sense to evaluate whether early treatment of prostate cancer with chemohormonal therapy directed against the androgen-dependent and -independent (presumably chemotherapy-sensitive) components of the disease could suppress clonal selection and the emergence of disease with anaplastic/small-cell features.

In conclusion, we believe that further improvement in therapy will come from understanding the biology of small-cell carcinoma, predicting its occurrence, and integrating new therapies into the treatment of this disease. The development of specific markers of SCPCa will be extremely valuable in the follow-up of patients with prostatic carcinoma, first as a prognostic tool but most importantly as a way to explore novel therapeutic targets (neutral endopeptidase-targeted therapy, growth factor inhibitors, and tyrosine kinase inhibitors) that will hopefully translate in improved clinical outcome.


   ACKNOWLEDGMENTS
 
Supported in part by the American Cancer Society grant no. CTRG-98-051-CCE (to C.N.P.).


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Tetu B, Ro JY, Ayala AG, et al: Small cell carcinoma of the prostate: Part 1—A clinicopathologic study of 20 cases. Cancer 59: 1803-1809, 1987[CrossRef][Medline]

2. Amato RJ, Logothetis CJ, Hallinan R, et al: Chemotherapy for small cell carcinoma of prostatic origin. J Urol 147: 935-937, 1992[Medline]

3. Oesterling JE, Hauzeur CG, Farrow GM: Small cell anaplastic carcinoma of the prostate: A clinical, pathological and immunohistological study of 27 patients. J Urol 147: 804-807, 1992[Medline]

4. Ro JY, Tetu B, Ayala AG, et al: Small cell carcinoma of the prostate: II. Immunohistochemical and electron microscopic studies of 18 cases. Cancer 59: 977-982, 1987[CrossRef][Medline]

5. Pearse AG, Takor T: Embryology of the diffuse neuroendocrine system and its relationship to the common peptides. Fed Proc 38: 2288-2294, 1979[Medline]

6. LeDouarin N, Teillet MA: The migration of neural crest cells to the wall of the digestive tract in the avian embryo. J Embryol Exp Morphol 30: 31-48, 1973[Medline]

7. Bonkoff H, Stein U, Remberger K: Endocrine-paracrine cell types in the prostate and prostatic adenocarcinomas are postmitotic cells. Hum Pathol 26: 167-170, 1995[CrossRef][Medline]

8. Schron DS, Gipson T, Mendelsohn G: The histogenesis of small cell carcinoma of the prostate: An immunohistochemical study. Cancer 53: 2478-2480, 1984[CrossRef][Medline]

9. Azzopardi JG, Evans DJ: Argentaffin cells in prostatic carcinoma: Differentiation from lipofuscin and melanin in prostatic epithelium. J Pathol 104: 247-251, 1971[CrossRef][Medline]

10. Helpap B, Kollermann J: Undifferentiated carcinoma of the prostate with small cell features: Immunohistochemical subtyping and reflections on histogenesis. Virchows Arch 434: 385-391, 1999[CrossRef][Medline]

11. Helpap B, Kollermann J, Oehler U: Neuroendocrine differentiation in prostatic carcinomas: Histogenesis, biology, clinical relevance, and future therapeutic perspectives. Urol Int 62: 133-138, 1999[CrossRef][Medline]

12. Bonkhoff H, Remberger K: Differentiation pathways and histogenetic aspects of normal and abnormal prostatic growth: A stem cell model. Prostate 28: 98-106, 1996[CrossRef][Medline]

13. Sella A, Kilbourn R, Amato R, et al: Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer. J Clin Oncol 12: 683-688, 1994[Abstract]

14. Ellerhorst JA, Tu S, Amato RJ, et al: Phase II trial of alternating weekly chemohormonal therapy for patients with androgen-independent prostate cancer. Clin Cancer Res 3: 2371-2376, 1997[Abstract/Free Full Text]

15. Pienta KJ, Redman B, Hussain M, et al: Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 12: 2005-2012, 1994[Abstract/Free Full Text]

16. Seidman AD, Scher HI, Petrylak D, et al: Etsramustine and vinblastine: Use of prostate specific antigen as a clinical trial end point for hormone refractory prostatic cancer. J Urol 147: 931-934, 1992[Medline]

17. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[CrossRef][Medline]

18. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10: 1-10, 1989[Medline]

19. Kaplan EL, Meier P: Nonparametric estimator from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef]

20. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 60: 163-170, 1966

21. Cox DR: Regression models and life tables (with discussion). J R Stat Soc B 34: 187-220, 1972

22. Therneau TM, Grambsch PM: Modeling Survival Data. New York, NY, Springer, 2000

23. Cleveland WS: Robust locally-weighted regression and smoothing scatterplots. J Am Stat Assoc 74: 829-836, 1979[CrossRef]

24. Therneau TM: A Package for Survival Analysis in S. Rochester, MN, Mayo Clinic Foundation, 1994

25. Kelly WK, Scher HI: Prostate specific antigen decline after antiandrogen withdrawal: The flutamide withdrawal syndrome. J Urol 149: 607-609, 1993[Medline]

26. Chute JP, Chen T, Feigal E, et al: Twenty years of phase III trials for patients with extensive-stage small cell lung cancer: Perceptible progress. J Clin Oncol 17: 1794-1801, 1999[Abstract/Free Full Text]

27. Trias I, Algaba F, Condom E, et al: Small cell carcinoma of the urinary bladder. Presentation of 23 cases and review of 134 published cases. Eur Urol 39: 85-90, 2001 (review)[CrossRef][Medline]

28. VanHaaften-Day C, Raghavan D, Russel P, et al: Xenografted small cell undifferentiated cancer of prostate: Possible common origin with prostatic adenocarcinoma. Prostate 11: 271-279, 1987[Medline]

29. Krijnen JL, Janssen PJ, Ruizeveld de Winter JA, et al: Do neuroendocrine cells in human prostate cancer express androgen receptor? Histochemistry 100: 393-398, 1993[CrossRef][Medline]

30. DiSant’Agnese PA, Cockett AT: Neuroendocrine differentiation in prostatic malignancy. Cancer 78: 357-361, 1996[CrossRef][Medline]

31. Gilbert F, Walop W, Chan J, et al: The role of the NH2-terminal portion of pro-opiomelanocortin as a biomarker for human lung cancer. Clin Invest Med 10: 372-375, 1987[Medline]

32. Reile H, Armatis PE, Schally AV: Characterization of high-affinity receptors for bombesin/gastrin releasing peptide on the human prostate cancer cell lines PC-3 and DU-145: Internalization of receptor bound 125I-(Tyr4) bombesin by tumor cells. Prostate 25: 29-38, 1994[Medline]

33. Baserga R: Insulin-like growth factor I receptor signaling in prostate cancer cells. Growth Horm IGF Res 10: S43-S44, 2000 (suppl A)

34. Kaplan PJ, Mohan S, Cohen P, et al: The insulin-like growth factor axis and prostate cancer: Lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Cancer Res 59: 2203-2209, 1999[Abstract/Free Full Text]

35. Nagaoka I, Someya A, Iwabuchi K, et al: Expression of insulin-like growth factor-IA and factor-IB in human liver, hepatoma cells, macrophage-like cells and fibroblasts. FEBS Lett 280: 79-83, 1991[CrossRef][Medline]

36. Bondy C, Lee WH: Patterns of insulin-like growth factor and IGF receptor gene expression in the brain: Functional implications. Ann N Y Acad Sci 692: 33-43, 1993 (review)[Medline]

37. Bracq S, Taboulet J, Machairas M, et al: Calcitonin mRNA is produced in liver by two different splicing pathways. Mol Cell Endocrinol 128: 111-115, 1997[CrossRef][Medline]

38. Fischer JA, Tobler PH, Henke H, et al: Salmon and human calcitonin-like peptides coexist in the human thyroid and brain. J Clin Endocrinol Metabol 57: 1314-1316, 1983[Abstract/Free Full Text]

39. Brawn PN: The dedifferentiation of prostate carcinoma. Cancer 52: 246-251, 1983[CrossRef][Medline]

40. Sehgal I, Powers S, Huntley B, et al: Neurotensin is an autocrine trophic factor stimulated by androgen withdrawal in human prostate cancer. Proc Natl Acad Sci U S A 91: 4673-4677, 1994[Abstract/Free Full Text]

41. Papandreou CN, Usmani B, Geng Y, et al: Neutral endopeptidase 24.11 loss in metastatic human prostate cancer contributes to androgen-independent progression. Nat Med 4: 50-57, 1998[CrossRef][Medline]

42. Bologna M, Festuccia C, Muzi P, et al: Bombesin stimulates growth of human prostatic cells in vitro. Cancer 63: 1714-1720, 1989[Medline]

43. Nelson JB, Chan-Tack K, Hedican SP, et al: Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer. Cancer Res 56: 663-668, 1996[Abstract/Free Full Text]

44. Nelson JB, Hedican SP, George DJ, et al: Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med 1: 944-949, 1995[CrossRef][Medline]

Submitted December 14, 2001; accepted April 10, 2002.


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