Treatment outcomes of small cell carcinoma of ... - Wiley Online Library

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Treatment Outcomes of Small Cell Carcinoma of the Prostate A Single-Center Study

Philippe E. Spiess, MD1 Curtis A. Pettaway, MD1 Funda Vakar-Lopez, MD2 Wassim Kassouf, MD1 Xuemei Wang, MS3 Joseph E. Busby, MD1 Kim-Anh Do, PhD3 Rajayogesh Davuluri, BS1 Nizar M. Tannir, MD4

BACKGROUND. The current study was conducted to determine the clinical characteristics and prognostic features associated with prostatic small cell carcinoma (SCC).

METHODS. Between January 1985 and May 2005, 83 patients with SCC of the prostate were identified. Univariate and multivariate Cox proportional hazards modeling were used to assess the prognostic significance of the clinical parameters associated with disease-specific outcomes.

RESULTS. Twenty-one patients had no evidence of distant metastasis at the time of the diagnosis of SCC, with the remaining patients demonstrating radiologic or biopsy-proven evidence of metastatic disease. Compared with patients with me-

1

Department of Urologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

tastases, patients without metastases at the time of diagnosis were older (P 5 .001) and had a lower serum lactate dehydrogenase (LDH) level at the time

2

and low serum albumin at the time of SCC diagnosis was found to be predictive

Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 3 Department of Biostatistics and Applied Mathematics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 4

Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

of diagnosis (P 5 .002). On multivariate analysis, an elevated serum LDH level of inferior progression-free survival (P 5 .02 and P 5 .008, respectively) and inferior disease-specific survival (DSS) (P 5 .02 and P 5 .01, respectively). At the time of last follow-up, 72 patients (87%) had died of disease, with a median DSS duration of 13.1 months (range, 10.7–17.1 months). There was a statistically significant difference noted with regard to the median DSS of patients with nonmetastatic versus those with metastatic SCC (17.7 months [95% confidence interval (95% CI), 12.1–39.2 months] vs 12.5 months [95% CI, 8.1–16.1 months], respectively; P 5 .03).

CONCLUSIONS. SCC of the prostate is a highly aggressive tumor, with serum LDH and albumin levels at the time of diagnosis believed to be predictive of diseaserelated outcomes. Although palliative, current systemic therapy does not result in cure and does not provide long-term survival for patients with metastases. For patients with nonmetastatic disease, a strategy utilizing systemic and local therapies should be evaluated further. Cancer 2007;110:1729–37. 2007 American Cancer Society.

KEYWORDS: prostate cancer, small cell carcinoma, prognosis, diagnosis.

S Address for reprints: Curtis A. Pettaway, MD, Department of Urology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; Fax: (713) 7944824; E-mail: [email protected] Received March 9, 2007; revision received April 24, 2007; accepted April 26, 2007.

ª 2007 American Cancer Society

mall cell carcinoma (SCC) of the urinary tract is a rare clinical entity, with scant information in the literature regarding its clinical behavior and optimal treatment. To our knowledge, the first documented case of SCC of the prostate was described by Wenk et al.1 in 1977. Since then, at least 130 other cases have been reported. However, the majority of these cases have been reported in case series, thereby limiting our ability to make definitive conclusions regarding the natural history and most effective treatment of this disease.

DOI 10.1002/cncr.22971 Published online 4 September 2007 in Wiley InterScience (www.interscience.wiley.com).

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October 15, 2007 / Volume 110 / Number 8

The clinical features of prostatic SCC differ from those of adenocarcinoma of the prostate in that SCC has a predilection to produce visceral metastases, lytic bony lesions, and low amounts of serum prostate-specific antigen (PSA).2 Although the etiology of prostatic SCC remains controversial, 3 theories have been proposed to date. The first theory postulates that SCC of the prostate originates from neuroendocrine cells.3 The second theory proposes that SCC of the prostate results from dedifferentiation of prostatic adenocarcinoma; the presence of PSA staining in some neuroendocrine cells appears to support this hypothesis.4,5 The third theory suggests that stem cells are the direct precursors of SCC of the prostate.6 Currently, it is unclear which of these theories correctly explains the pathogenesis of SCC of the prostate. Oesterling et al.7 reported what to our knowledge is 1 of the largest series of SCC of the prostate presented to date, with 27 patients treated over a 30year period. Of the 24 patients with long-term follow-up, 92% died while receiving androgen deprivation therapy (ADT). The median overall survival duration from the time of diagnosis of SCC was 17.1 months (range, 2–90 months). In a previous report from our institution,8 11 of 20 patients with SCC of the prostate had died of the disease. In a phase 2, prospective study conducted at our center in which 38 patients with metastatic SCC of the prostate were treated with 4 cycles of doxorubicin, cisplatin, and etoposide, the overall response rate was 61% and the median overall survival duration was 10.5 months.9 Combined, these studies demonstrate the aggressive behavior of SCC of the prostate; however, there is insufficient information concerning the prognostic features underlying its progression and survival. In the current study, we report our experience in the management of SCC of the prostate over the past 20 years, focusing on the predictors of outcome in this patient population. In addition, we present the treatment-related outcomes of patients with nonmetastatic disease at the time of SCC diagnosis, and we appraise the potential merits of local therapy in this subgroup of patients.

MATERIALS AND METHODS Study Design Before conducting the current study, a retrospective chart review protocol was designed and approved by The University of Texas M. D. Anderson Cancer Center Institutional Review Board. Between January 1985 and May 2005, 103 patients were diagnosed with SCC of the prostate at the M. D. Anderson Cancer

Center; 20 cases were excluded from the current study because they did not meet the histologic criteria used to define SCC of the prostate. The remaining 83 patients constituted our study population and were entered into a retrospective clinical database. The diagnosis of SCC was determined on the basis of the presence of undifferentiated carcinoma histology that demonstrated small-sized to medium-sized cells with a minimal amount of cytoplasm and hyperchromatic, overlapping nuclei with no or few nucleoli, as observed in SCC of other organs. Immunohistochemical stains (PSA; prostatic acid phosphatase; cytokeratin; and neuroendocrine markers such as chromogranin A, synaptophysin, and CD56) were used to support the diagnoses of SCC of the prostate when tissues were available. Cases in which the diagnosis of SCC of the prostate was suspected clinically as constituting metastasis to the prostate from SCC of nonprostatic origin were excluded. Diagnostic evaluation of SCC of the prostate at our center consisted of a complete medical history, physical examination, laboratory investigations, transrectal ultrasonography (TRUS) of the prostate with biopsies (if not previously performed), and radiologic imaging (chest X-ray, computed tomography scan of the abdomen and pelvis, and bone scan). Additional imaging modalities were obtained by the treating physician on an individual basis. All patients were staged using the 1997 TNM staging system. To confirm the original diagnosis of SCC of the prostate, all pathology reports were reviewed by a single genitourinary pathologist (F.V.L.) to confirm the diagnosis of SCC of the prostate; however, 23 cases in which the diagnosis was questioned based on interpretation of the prior histopathology report by our pathologist were rereviewed in detail to verify the diagnosis as SCC of the prostate.

Statistical Analysis Descriptive statistics such as the median (range) for continuous variables and frequency (percentage) for categoric variables were used to summarize the distribution of diagnostic, treatment-related, and disease-related variables. The pairwise association between continuous variables was assessed using the Spearman correlation coefficient. The 2 study endpoints were progression-free survival (PFS) and disease-specific survival (DSS). For the analysis of DSS, disease-specific death was the only event noted, with patients who survived being censored at the time of last follow-up. For the analysis of PFS, disease progression or recurrence, as demonstrated by pathology or radiologic imaging, were defined as events. DSS

Prostatic Small Cell Carcinoma Treatment/Spiess et al.

duration was calculated from the date of the diagnosis of SCC to the date of disease-specific death; the duration of PFS was calculated from the date of diagnosis of SCC to the date of disease progression, as documented by imaging studies or tissue biopsy. The method of Kaplan and Meier was used to estimate the PFS or DSS probabilities.10 Univariate and multivariate Cox proportional hazards models were used to assess the impact of the various clinical parameters on PFS or DSS. To further characterize the outcome of patients on the basis of serum albumin and lactate dehydrogenase (LDH) levels, patients were defined as having a low or high serum level of albumin or LDH using their respective medians as the cutoff values. The log-rank test was used to assess the difference in PFS or DSS among 4 groups of patients defined based on low or high albumin or LDH values. All statistical analyses were performed using S-PLUS software (Insightful Corporation; Seattle, Wash), with P values < .05 deemed statistically significant.

RESULTS Patient Characteristics The patients’ characteristics are summarized in Table 1. On prostate biopsy, 30 patients (36%) were shown to have pure SCC of the prostate and 53 patients (64%) had mixed SCC and adenocarcinoma. The biopsy Gleason score in those patients with mixed histology was most commonly poorly differentiated, defined as a Gleason score 8 (46 patients [87%]). Twenty-seven patients (33%) had de novo SCC, with no prior history of prostate cancer; the remaining 56 patients (67%) had prostatic adenocarcinoma before the development of SCC. Of those 56 patients, 52 (93%) had received prior ADT, with a median interval of 30 months (range, 4 months-10 years) from the initiation of ADT to the diagnosis of SCC. At the time of SCC diagnosis, 21 (25%) of the 83 patients had no evidence of metastatic disease, and 62 patients (75%) had radiologic-proven or biopsyproven metastases. The most common sites of metastases were bone (37 patients), retroperitoneal lymph nodes (17 patients), liver (16 patients), and lungs (11 patients). Eight patients (10%) developed brain metastases. The majority of patients had either 1 (44 patients) or 2 (12 patients) sites of metastasis. Sixty-eight patients (82%) had local symptoms at the time of SCC diagnosis (lower urinary tract symptoms in 32 patients, bladder outlet obstruction in 18 patients, pelvic pain in 12 patients, ureteral obstruction in 4 patients, and macroscopic hematuria in 2 patients).

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TABLE 1 Patient Characteristics (n 5 83) Variable Age at diagnosis of prostate carcinoma, y PSA at presentation, ng/mL Clinical T classification T1 T2 T3 T4 Tx SCC Pure Mixed Biopsy Gleason score* 7 8 Age at diagnosis of SCC, y Prior history of adenocarcinoma of the prostate No Yes Prior ADT before SCC Yes No Time from start of ADT, mo Clinical presentation of SCC Lower urinary tract symptoms Bladder outlet obstruction Bone pain Pelvic pain Ureteral obstruction Macroscopic hematuria No. of metastatic sites 0 1 2 3 Sites of metastasis Bone Retroperitoneal lymph nodes Liver Lung Brain Treatment of SCC Chemotherapyy alone Chemotherapy plus ADT Radiotherapy plus chemotherapyy plus ADT Surgery plus chemotherapyy plus ADT ADT alone Supportive care

No.

Median (range) 63 (40–82) 10 (0.9–603)

10 (12%) 21 (25%) 37 (45%) 6 (7%) 9 (11%) 30 (36%) 53 (64%) 7 (13%) 46 (87%) 66 (40–86) 27 (33%) 56 (67%) 52 (63%) 31 (37%) 30 (4–120) 32 (39%) 18 (22%) 15 (18%) 12 (15%) 4 (5%) 2 (2%) 21 (25%) 44 (53%) 12 (15%) 6 (7%) 37 (42%) 17 (19%) 16 (18%) 11 (12%) 8 (9%) 38 (46%) 29 (35%) 6 (7%) 3 (4%) 1 (1%) 6 (7%)

PSA indicates prostate-specific antigen; SCC, small cell carcinoma; ADT, androgen deprivation therapy. * Gleason score not assigned to cases of pure SCC. y Chemotherapy consisted of etoposide and/or a platinum compound in 68 of these 76 patients (89%).

The most common form of initial therapy for SCC of the prostate was systemic chemotherapy, given either alone (38 patients), combined with ADT (29 patients), combined with radiotherapy and ADT

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TABLE 2 Clinical and Laboratory Parameters of Patients With and Without Metastases at Diagnosis of SCC of the Prostate (n 5 83)

Variable

Nonmetastatic SCC at diagnosis (n 5 21), median (range)

Metastatic SCC at diagnosis (n 5 62), median (range)

P

Age at diagnosis with SCC, y Time from ADT to SCC, mo Hemoglobin, g/dL White blood cell count, 3103/lL Platelet count, 3103/L Creatinine, mg/dL PSA, ng/mL LDH, IU/L Corrected calcium, mg/dL Alkaline phosphatase, IU/L Albumin, g/dL CEA, ng/mL

71 (54–84) 40 (4–147) 12.5 (7.9–15.2) 9.1 (4.1–15.7) 279.5 (9.9–714) 0.45 (0.10–78.1) 1.1 (0.8–1.8) 520 (351–896) 9.9 (8.5–10.8) 108.5 (60.0–1797) 4.0 (3.0–4.6) 4.5 (0.1–321)

63.5 (40–86) 27 (0–141) 11.9 (8.4–16.8) 8.0 (2.9–31.8) 264.5 (87–552) 1.2 (0.1–283) 1.0 (0.5–2.8) 788 (379–5665) 10.0 (7.3–19.3) 118.5 (37–893) 4.0 (2.4–4.8) 7.8 (1.0–5214)

.001 .59 .33 .47 .44 .29 .19 .002 .67 .41 .33 .79

SCC indicates small cell carcinoma; ADT, androgen deprivation therapy; PSA, prostate-specific antigen; LDH, lactate dehydrogenase; CEA, carcinoembryonic antigen.

(6 patients), or combined with surgery and ADT (3 patients), for a total of 76 patients. Sixty-eight of these 76 patients (89%) received regimens containing etoposide and/or a platinum compound, whereas the remaining 8 patients (11%) received other chemotherapeutic regimens. Only 4 of the 21 patients (19%) who had no evidence of metastatic disease at the time of diagnosis of prostatic SCC received local therapy in addition to systemic therapy. Local therapy in those 4 patients was comprised of radical cystoprostatectomy (3 patients) and external beam radiotherapy (1 patient). The 3 patients who had undergone a cystoprostatectomy also had received neoadjuvant chemohormonal therapy before surgery; however, they all developed distant metastases. As of the date of last follow-up, 2 of these 3 patients had died of SCC; the mean DSS duration for the 3 patients who underwent cystoprostatectomy was 4.0 years (range, 1.8–6.1 years) from the date of surgery. The patient who was treated with definitive external beam radiotherapy had also received neoadjuvant and adjuvant ADT and was alive with no evidence of disease at the time of last follow-up, 1.3 years after radiotherapy. Three of these 4 patients had local symptoms (lower urinary tract symptoms in 2 patients and urinary obstruction/pelvic pain in 1 patient) at the time of the diagnosis of SCC, but their symptoms resolved after local therapy. In contrast, of the 47 patients with metastatic SCC at the time of diagnosis, only 5 (11%) had a noticeable improvement in their symptoms with systemic therapy alone (3 patients had lower urinary tract symptoms and 2 patients had pelvic pain). One of these patients

later received pelvic radiotherapy for symptomatic control.

Laboratory Data The median serum PSA level at the time of the diagnosis of SCC was 1.1 ng/mL, and none of the patients had an elevated serum PSA level (>4 ng/ mL). The majority of patients had a normal serum creatinine level at the time of SCC diagnosis, with a median serum creatinine level of 1.0 mg/dL. The median serum albumin, LDH, and carcinoembryonic antigen (CEA) levels at the time of diagnosis were 4 g/dL, 664 IU/L, and 5.4 ng/mL, respectively. A weak colinear association was noted between serum LDH and alkaline phosphatase levels, with a Spearman correlation coefficient between these 2 variables of 0.38 (P 5 .002). Nonmetastatic Versus Metastatic SCC A comparison of the clinical, laboratory, and pathologic variables of patients with or without metastatic disease at the time of the diagnosis of prostatic SCC is shown in Table 2. Patients with nonmetastatic disease at the time of SCC diagnosis were significantly older (median age of 71 years vs 63.5 years; P 5 .001) and had a significantly lower serum LDH level at diagnosis (520 IU/L vs 788 IU/L; P 5 .002). No significant differences were noted between patients with nonmetastatic disease and those with metastatic disease with regard to their serum PSA (P 5 .19) and CEA (P 5 .79) levels. The absence of metastatic disease at the time of SCC diagnosis was associated with longer PFS and DSS (Figs. 1 and 2, respectively).


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FIGURE 1. Kaplan-Meier estimates of progression-free survival by meta-

FIGURE 3. Kaplan-Meier estimates of progression-free survival for all

static status (Mets) at diagnosis (Dx).

patients (n 5 83). 95% C.I. indicates 95% confidence interval.

TABLE 3 Univariate Cox Proportional Hazards Model for Progression-Free Survival (n 5 83) Variable

Coefficient

SE

RR

P

Hemoglobin log(creatinine) log(LDH) log(alkaline phosphatase) Albumin Presence of metastasis at SCC diagnosis

20.182 0.131 0.600 0.316 20.837

0.068 0.066 0.184 0.155 0.249

0.833 1.140 1.820 1.370 0.433

.008 .05 .001 .04 .001

0.542

0.271

1.720

.05

SE indicates standard error; RR, relative risk; LDH, lactate dehydrogenase; SCC, small cell carcinoma.

FIGURE 2. Kaplan-Meier estimates of disease-specific survival by metastatic status (Mets) at diagnosis (Dx).

TABLE 4 Multivariate Cox Proportional Hazards Model for Progression-Free Survival (n 5 83)

The median PFS time for patients with nonmetastatic and those with metastatic SCC at the time of diagnosis was 10 months and 5 months, respectively.

Variable

Coefficient

SE

RR

P

log(LDH) Albumin

0.47 20.68

0.20 0.25

1.59 0.51

.02 .008

PFS Analysis Overall, disease progression developed in 80 patients (96%), with a median PFS duration of 6 months (Fig. 3). On univariate analysis, several potential predictors of PFS were identified, including hemoglobin, log (serum creatinine level), log (serum LDH level), log (serum alkaline phosphatase level), serum albumin level, and the presence of metastasis at time of SCC diagnosis (Table 3). However, on multivariate analysis, only serum albumin level and log (serum LDH level) at the time of SCC diagnosis were found to be significant predictors of PFS (P 5 .008 and P 5 .02, respectively), as shown in Table 4. Patients who had a low serum albumin level and a high serum LDH level were found to have a significantly shorter duration of PFS, with a median PFS of only

SE indicates standard error; RR, relative risk; LDH, lactate dehydrogenase.

1.3 months compared with all other patients, whose median PFS ranged from 7.5 to 10.7 months (P < .0001).

DSS Analysis As shown in Figure 4, 72 patients (87%) had died of prostatic SCC at the time of last follow-up, with a median DSS of 13.1 months (range, 10.7–17.1 months). There was a significant difference noted with regard to DSS in patients with nonmetastatic compared with patients with metastatic SCC at the time of diagnosis (median DSS of 17.1 months [95%

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FIGURE 4. Kaplan-Meier estimates of disease-specific survival for all patients (n 5 83). 95% C.I. indicates 95% confidence interval.

FIGURE 5. Kaplan-Meier estimates of disease-specific survival probabilities by serum albumin (Alb)s and lactate dehydrogenase (LDH) subgroups.

TABLE 5 Univariate Cox Proportional Hazards Model for Disease-Specific Survival (n 5 83) Variable

Coefficient

SE

RR

P

Hemoglobin Log(LDH) Log(alkaline phosphatase) Albumin De novo vs secondary dedifferentiation to SCC Presence of metastasis at time of SCC diagnosis Primary therapy of SCC, chemotherapy vs others

20.148 0.435 0.449 20.847

0.074 0.169 0.165 0.283

0.862 1.550 1.570 0.429

.05 .01 .007 .003

20.514

0.266

0.598

.05

0.592

0.287

1.810

.04

0.930

0.439

2.530

.03

TABLE 7 Disease-Specific Survival Classified According to Serum Albumin and LDH Levels Using the Median as a Cutoff Value Group

No.

No. of events

Median DSS, months

95% CI

P

Low albumin, low LDH Low albumin, high LDH High albumin, low LDH High albumin, high LDH

14 17 19 16

13 15 18 12

17.6 4.0 14.4 17.1

10.0-NA 2.6-NA 9.3–24.1 12.5-NA

< .0001

LDH indicates lactate dehydrogenase; DSS, disease-specific survival; 95% CI, 95% confidence interval; NA, not attained.

SE indicates standard error; RR, relative risk; LDH, lactate dehydrogenase; SCC, small cell carcinoma.

TABLE 6 Multivariate Cox Proportional Hazards Model for Disease-Specific Survival (n 5 83) Variable

Coefficient

SE

RR

P

log(LDH) Albumin

0.40 20.70

0.17 0.28

1.49 0.50

.02 .01

SE indicates standard error; RR, relative risk; LDH, lactate dehydrogenase.

CI, 12.1–39.2 months] vs 12.5 months [95% CI, 8.1– 16.1 months], respectively; P 5 .03). On univariate analysis, potential predictors of DSS included serum hemoglobin level, log (serum LDH level), log (serum alkaline phosphatase level), serum albumin level, prior history of prostatic adenocarcinoma, presence of metastatic disease at time of SCC diagnosis, and chemotherapy as the primary treatment of SCC (Table 5). On multivariate analysis and as shown in Table 6, only the serum albumin level and log (serum

LDH level) were found to be significant predictors of the duration of DSS (P 5 .01 and P 5 .02, respectively). As shown in Figure 5, patients who had a low serum albumin level and a high serum LDH level had a significantly shorter duration of DSS, with a median DSS of only 4.1 months, compared with all other patients whose median DSS durations ranged from 14.4 to 17.7 months (P < .0001) (Table 7). None of the patients with nonmetastatic SCC at the time of diagnosis had both a low serum albumin level and a high LDH level.

DISCUSSION In the current study, we confirmed the adverse prognosis associated with a diagnosis of SCC of the prostate, demonstrating a disease-specific mortality rate approaching 90% and a median DSS duration of 13.1 months. Of the clinical and laboratory variables evaluated, elevated serum LDH and low serum albumin


levels were identified on multivariate analysis as being significant predictors of inferior PFS and DSS. One of the limitations of the current study is that our patient database was retrospectively collected, thereby potentially introducing a selection bias into our study. In a previous study of 38 patients with SCC of the prostate, performance status, low serum albumin level, and number of metastatic sites were identified as predictors of outcome.9 Our larger study validates the importance of a low serum albumin level in predicting inferior disease-related outcomes in this patient population. However, our study could not validate the prognostic signifcance of performance status in predicting PFS or DSS within this patient population. In the current study, the use of systemic chemotherapy was not found to be a predictor of PFS and DSS because the majority of patients (92%) received it as initial therapy. Patients with nonmetastatic disease at the time of SCC diagnosis presented at an older age and had a lower serum LDH level compared with patients who had metastatic disease at the time of diagnosis of SCC. None of the patients with nonmetastatic SCC at the time of diagnosis were found to have both a low serum albumin and a high serum LDH level, further supporting the notion that these serologic markers reflect tumor burden. Furthermore, the results of the current study clearly demonstrate that patients with a combination of a low serum albumin level and a high LDH level at the time of diagnosis have a poorer PFS and DSS than other patients with SCC of the prostate. However, the poor prognosis associated with the combination of a low serum albumin level and a high serum LDH level at the time of diagnosis of SCC may be valid only for patients with metastatic disease at the time of presentation with SCC. Previous studies have reported on the prognostic value of serum LDH11–13 and serum albumin14 levels in other genitourinary organs or other sites of disease; however, the current study validates the clinical significance of these variables for SCC of the prostate. Although the majority of patients treated at our institution had metastatic disease at the time of their diagnosis of SCC, there was a statistically significant survival benefit to having nonmetastatic disease at the time of SCC diagnosis. This advantage may reflect a lead-time bias because of cancer detection occurring at an earlier stage in its evolution. Another explanation may be that, in patients who present with local disease, the disease is biologically different and is associated with a low serum LDH level and occurs in older subjects. In support of this argument, we noted that the median time to metastatic disease

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progression in patients with nonmetastatic SCC at the time of diagnosis was 26 months. In this retrospective review, we were surprised to find that only 20% of patients with nonmetastatic disease at the time of SCC diagnosis received local therapy in addition to systemic therapy. Although it is inappropriate to make inferences regarding the role of local therapy in the management of SCC of the prostate based on a small number of cases (of the 21 patients with nonmetastatic disease at the time of diagnosis, 3 patients underwent a cystoprostatectomy and 1 received definitive external beam radiotherapy), we and others15 believe that surgical resection with or without external beam radiotherapy should be evaluated further as treatment strategies for select patients with nonmetastatic SCC of the prostate because they may provide better local control and a potential survival benefit when combined with systemic therapy compared with systemic therapy alone. As has been previously published, SCC of the prostate can appear de novo without a prior history of prostate cancer or can develop in patients after a history of prostatic adenocarcinoma, usually of high grade.2,8 In the current study, approximately twothirds of the patients developed SCC of the prostate after a prior history of prostatic adenocarcinoma, and nearly all of these patients had received prior ADT for a period of several years. Thus, the development of SCC could be the result of adaptive dedifferentiation of prostatic adenocarcinoma subsequent to treatment with ADT or the selective outgrowth of rare clonal populations.16 Because the majority of prostatic adenocarcinomas do not become SCC subsequent to ADT, it is conceivable that prostate cancers possess multipotential stem cells that can manifest as SCC under the selection pressure of ADT or as-yet unidentified genetic and epigenetic factors related to the oncologic niche of the tumor.17 Further definition of the molecular phenotype of pathologically defined SCC may aid in potentially defining mechanisms of resistance to therapy and this also may have prognostic and/or predictive implications. In conjunction with a report by Rubenstein et al.,18 the current study demonstrates the propensity for SCC of the prostate to metastasize to visceral organs, with bone, retroperitoneal lymph nodes, liver, and lungs being the most common sites of distant metastasis. Furthermore, the majority of patients in the current study had a low serum PSA level at the time of diagnosis of SCC, thereby illustrating the scenario that prostate cancer that does not respond to conventional treatment regimens or that with un-

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usual sites of metastases should be considered as potentially being of SCC histology, especially if the serum PSA level is low.19 Although CEA has been previously evaluated as a useful tumor marker in patients with SCC of the prostate, to our knowledge it has not been demonstrated to be an independent predictor of disease-related outcomes.9 In the current study, we identified elevated serum LDH and low serum albumin levels as important predictors of poor outcome in patients with metastatic SCC of the prostate. Patients with a low serum albumin level and a high serum LDH level were found to have median PFS and DSS durations of 1.3 months and 4.1 months, respectively. This finding clearly illustrates that this subset of patients has a propensity for rapid disease progression and death, despite currently available treatment strategies aimed at palliation, thus underscoring the need to find more effective treatment options for these patients. To our knowledge, the optimal treatment strategy for SCC of the prostate has yet to be determined. This uncertainty is largely due to the rarity and highly aggressive phenotype of this entity, irrespective of treatment approach. The scientific literature evaluating the treatment outcomes of patients with SCC of nonprostatic origin reveal that aggressive, dose-intensified chemotherapy regimens offer a therapeutic benefit, albeit one potentially associated with increased toxicity.20 Other studies have proposed that multimodality therapy using a combination of chemotherapy and radiotherapy may offer an improved therapeutic benefit.21 In a study of nonmetastatic SCC of the bladder from our institution, patients treated with 4 cycles of neoadjuvant chemotherapy (doxorubicin plus ifosfamide alternating with etoposide plus cisplatin) followed by radical cystectomy yielded a 4-year DSS rate of 70%.22,23 A similar approach to the management of patients with nonmetastatic SCC of the prostate using systemic therapy with ADT and chemotherapy followed by radical cystoprostatectomy may improve the outcome of this subset of patients. SCC of the prostate represents an aggressive tumor histology that is associated with high diseasespecific mortality. Patients who present with a low serum albumin level and a high serum LDH level at the time of initial diagnosis appear to have a dismal prognosis and therefore should be offered alternative therapies as soon as possible after symptom control is achieved with conventional chemohormonal therapy. For the subgroup of patients with nonmetastatic disease at the time of SCC diagnosis, there may be a benefit to incorporating local therapies with systemic therapy, but this treatment

approach should be evaluated further in future prospective multicenter trials.

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