Oncologist. The. N ews B ulletin. Cancer Medicine: Case Discussions. Progressing Prostate Carcinoma. Joan Karnell Cancer Center Pennsylvania Hospital

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1 The Oncologist N ews B ulletin Cancer Medicine: Case Discussions Joan Karnell Cancer Center Pennsylvania Hospital Progressing Prostate Carcinoma MICHAEL J. HAUT, JOSEPH F. HARRYHILL, JEFFREY ROSENSTOCK, MICHAEL J. WARHOL, RICHARD VITTI Pennsylvania Hospital, Philadelphia, Pennsylvania, USA Key Words. Prostate cancer Chemotherapy Radiation therapy Urologic surgery Hormonal therapy Adjuvant therapy ABSTRACT In the Karnell Cancer Center Grand Rounds, we present a patient who underwent radical prostatectomy with bilateral pelvic lymphadenectomy, but had positive margins and subsequently developed local recurrence and then systemic disease. Pathologic and radiologic aspects of his disease are discussed. Therapeutic options at different stages of the disease are examined from the point of view of the urologist, radiation oncologist, and medical oncologist. The surgical portion of the discussion focuses on the selection of initial therapy. Both the selection of surgical candidates and choice of pre- or post-operative therapy in patients can be aided by prognostic tools looking at several variables, including prostate-specific antigen (PSA) level, Gleason score of the tumor, seminal vesicle invasion, extracapsular invasion, and lymph node involvement. Low-risk patients can be treated with monotherapy, such as radical prostatectomy, external beam radiation therapy, prostate brachytherapy, or cryosurgical ablation of the prostate. Higher risk patients may require adjuvant and possibly neoadjuvant therapy in addition. The radiation portion of the discussion focuses on the use of radiation therapy as salvage for relapsing disease. Of particular importance is the point that treating highrisk patients whose PSA levels have started to rise but are less than 1 ng/ml results in a long-term PSA control rate as high as 75%, but that limiting the use of salvage radiation therapy to patients with high PSA levels or biopsy confirmation of local recurrence in the face of a negative bone scan results in biochemical long-term control of less than 40%. In the medical oncology part of the discussion, the major focus is on the use of chemotherapy to treat patients whose disease has become resistant to hormonal therapy. Mitoxantrone plus a corticosteroid has been found to offer significant palliation for such patients. Combination therapy with estramustine plus taxanes, other microtubule inhibitors, or other agents such as topoisomerase II inhibitors, has been found to cause shrinkage of measurable soft tissue disease and diminution of serum PSA levels. The development of effective hormonal and chemotherapeutic drugs for treatment of metastatic disease has led to new interest in adjuvant and neoadjuvant therapy of high-risk patients. The Oncologist 2001;6: INTRODUCTION As the ability of surgeons, radiation oncologists, and medical oncologists to manage more complicated and previously refractory tumors has improved, patient management has become more of an interdisciplinary effort. To reflect this, our center holds an interdisciplinary oncology grand rounds every other month to address a particular patient management problem in detail. This is a more formal reflection of what all oncology programs, including ours, do on a daily basis. CASE PRESENTATION A 68-year-old man was found in December 1991 to have a nodule in the left lobe of his prostate on digital rectal examination, and an elevated prostate-specific antigen (PSA) of 6.9. Correspondence: Michael J. Haut, M.D., Karnell Cancer Center, 230 West Washington Square, Philadelphia, Pennsylvania 19106, USA. Telephone: ; Fax: ; mjhaut@juno.com Received November 17, 2000; accepted for publication February 28, AlphaMed Press /2001/$5.00/0 The Oncologist 2001;6:

2 Haut, Harryhill, Rosenstock et al. 184 Prostate ultrasound revealed a hypoechoic left peripheral zone mass. Multiple needle biopsies of his prostate (random sampling) in January 1992 revealed benign prostatic hyperplasia. In February 1992, he underwent ultrasound-guided needle biopsy of his prostate. Biopsy of the left basal region revealed prostatic adenocarcinoma, Gleason pattern A computed axial tomography (CAT) scan of the abdomen and pelvis was negative, and a bone scan showed no evidence of metastatic disease. In March 1992, he underwent pelvic lymph node dissection and radical retropubic prostatectomy. Pathologic findings were: adenocarcinoma involving left lobe of prostate and distal resection margin; proximal margin negative for tumor; left and right obturator lymph nodes (four each) negative for tumor, and seminal vesicles free of tumor. Following surgery his PSA dropped to 0.2 (May 1992). However, by July 1992, it was 0.6. By November 1992, his PSA was 1.5. Ultrasound in November 1992 revealed a soft tissue mass in the prostate bed measuring cm. Needle biopsy at that time was suspicious for recurrent prostate adenocarcinoma. His PSA continued to rise and in February 1993 was 2.7. A CAT scan in March 1993 was negative except for the known prostatic bed nodule, and a bone scan at that time was negative. He was treated with 6,600 cgy delivered to the prostate bed in 33 fractions over 49 elapsed days. Following radiation therapy, his mass was no longer palpable on digital rectal examination. His PSA did not become undetectable, but remained in the low 2s. By January 1994, it had risen to 4.2, and in April 1994 it was A bone scan in May 1994 showed new metastatic disease in the L4 vertebra. He remained asymptomatic, and did not wish to take any systemic therapy at that time. In July 1994, he developed right groin pain. A bone scan at that time showed the known metastatic disease in his L4 vertebra, and bone plain films showed vertebral collapse at L4. His PSA in July 1994 was 11.9, and rose to 35.2 on October 25, He was started on leuprolide in November Following this, his PSA diminished, and remained below 1 until April 1997, when it rose to A bone scan done in March 1997 showed stable disease, and a CAT scan showed no evidence of metastatic or residual prostate carcinoma. In July 1997, his PSA was 5.9. He started flutamide in June 1997, but switched to bicalutamide in October 1997 because of diarrhea. His PSA initially remained stable, in the 5 to 6 range, but subsequently began to rise in By July 1998, the PSA had risen to 87.9, and he developed a pathologic fracture of L4 with an associated soft tissue mass on CAT scan. He was irradiated to the L4 region, and was entered subsequently on an experimental protocol with the hormone toremifine. However, his disease continued to progress, with rising PSA levels and progression of disease on the bone scan. In January 1999, he was placed on a chemotherapy protocol that included prednisone, mitoxantrone, and either a matrix metalloproteinase inhibitor (AG3340) or placebo. Prior to initiation of the chemotherapy, his bone scan showed progression of bony metastatic disease, and a CAT scan showed bilateral common iliac lymphadenopathy and recurrent disease in the prostate bed. His PSA in January 1999 was On the chemotherapy, his PSA gradually dropped to a level of 2.2 by June A CAT scan of the abdomen and pelvis done in April 2000 revealed no evidence of local or regional recurrence. A bone scan done at the same time showed increased uptake in the thoracic spine and the left sacral ala. These were shown on the magnetic resonsance imaging (MRI) to be consistent with osteoporotic compression fractures. He has required no radiation therapy to any bony lesions since At present, he is pain-free. PATHOLOGY (DR. MICHAEL WARHOL) Pathology from the prostatectomy specimen (Fig. 1) reveals adenocarcinoma with glands infiltrating profusely through smooth muscle. There is no nodule formation. Figure 2 is a Figure 1. Prostate carcinoma (25, Hematoxylin and Eosin). Low power photomicrograph of prostate adenocarcinoma. Gleason grade Figure 2. Prostate adenocarcinoma (100, Hematoxylin and Eosin). Prostatic adenocarcinoma with variable growth pattern.

3 185 Progressing Prostate Carcinoma Figure 3. Prostate adenocarcinoma (250, Hematoxylin and Eosin). Malignant prostate glands infiltrating smooth muscle at the resection margins. Figure 4. Prostate adenocarcinoma (100, Hematoxylin and Eosin). Prostatic adenocarcinoma exhibiting perineural invasion. higher power photomicrograph illustrating a characteristic histopathology of malignancy. There is a back-to-back or glandwithin-gland pattern. Adjacent glands lack intervening stroma. This pattern alone is diagnostic of malignancy. Other areas of the tumor (Fig. 3) have distended glands filled with cells in a gland-within-gland pattern with central necrosis. This pattern is reminiscent of comedo carcinoma of the breast. The top left corner (arrow) indicates the resection margin, where tumor is present. Peripheral nerves are encased by malignant prostate glands (Fig. 4). This is not an uncommon finding in prostate cancer and indicates an aggressive lesion. There is also lymphatic involvement. The pattern of growth for this tumor is different in different areas. These different growth patterns are the basis for the Gleason grading system [1, 2] which assigns numbers to different patterns of growth. This system is based on architectural patterns rather than cytologic features. One grades the primary (most prevalent) and secondary (second most prevalent) architectural patterns, and assigns a grade from 1 to 5 to each of the two areas, with 1 being the most differentiated and 5 being undifferentiated. The Gleason sum is reported as two numbers, with the primary grade first (i.e., 3 + 4, 2 + 3, etc), which allows distinction of severity in tumors with the same Gleason sum. The usefulness of the Gleason sum is related to the fact that, when the primary and secondary patterns differ, prognosis is intermediate between that predicted by either of the two patterns. As with prognostic indicators for most carcinomas, Gleason sums break down into three prognostic groups: good (2-4), bad (8-10), and intermediate (5-7). Markers that can be detected histochemically may be useful in predicting the behavior of prostatic lesions. None of these is U.S. Food and Drug Administration-approved for use on prostatic specimens. One such marker is the Her- 2/neu oncogene. This is identical to the C-erb B-2 oncogene and represents an epidermal growth factor receptor. Amplification or overexpression of this oncogene may correlate with aggressive behavior. Amplification of this oncogene may be detected by fluorescence in situ hybridization (FISH) and overexpression by immunoperoxidase techniques [3-5]. FISH analysis is thought to be the more reliable method. Using FISH, the degree of amplification correlates with the grade of the tumor and its ploidy status. Gene amplification also correlates with recurrence rate and is present in 75% of tumors with metastases [6, 7]. FISH is also an excellent method of detecting aneuploidy. It allows signals from individual chromosomes to be easily counted. Thus far, a consistent abnormality has not been demonstrated in prostatic adenocarcinomas. However, chromosomes 7, 8, 9, and 17 are the ones most commonly abnormal [8, 9]. RADIOLOGY (DR. RICHARD VITTI) Adenocarcinoma of the prostate is initially evaluated by digital rectal examination and measurement of PSA. Thereafter, evaluation of the prostate gland by transrectal ultrasonography is helpful, particularly if a hypoechoic mass can be identified, although some tumor masses may be isoechoic or hyperechoic [10]. Transrectal ultrasonography can be used to guide needle biopsies of suspicious areas. Following cryotherapy, surgery, or radiation therapy, there may be fibrosis or distortion of the tissue planes, and ascertaining the presence of recurrent disease may be difficult. Cross sectional CT [11, 12] and MRI may be helpful in judging spread of disease beyond the prostatic capsule, detecting visceral and lymph node metastases, and identifying osteoblastic metastases in nearby bones using specific imaging windows. Involvement of regional lymph nodes by prostatic cancer is crucial in guiding treatment, particularly in the use of external beam radiation therapy (EBRT). Generally, lymph nodes measuring greater than 1 cm are deemed suspicious, and may be sampled by fine needle aspiration biopsy.

4 Haut, Harryhill, Rosenstock et al. 186 MRI can be employed in the evaluation of local and distant prostatic cancer, and image spatial resolution is improved when specific endorectal surface coils are used. The overall accuracy of MRI is not yet established, and imaging may be hampered by lengthy scan acquisition times and patient motion. Radionuclide bone imaging with technetium-99m-methylene diphosphonate is the mainstay in the evaluation of metastatic disease from prostate cancer due to its high sensitivity [13]. Preferential colonization of the bone marrow by prostatic cancer is due to the passage of cancer cells through Batson s paravertebral venous plexus. Therefore, the axial skeleton is usually first involved, and the incidence by clinical stage is given in Table 1. The incidence by site is given in Table 2. Skeletal metastases appear as foci of intense abnormal radiotracer uptake on bone scans. A single lesion may be difficult to characterize, and examination by radiographic plain film or MRI may be necessary to ascertain its nature. Multiple lesions or diffuse skeletal involvement (a superscan ) are easier to characterize as metastatic involvement of the skeleton. Other lesions common in older males, such as Paget s disease, old trauma, or degenerative joint disease, may be mistaken for metastatic involvement. Rarely, large lytic lesions may not be well seen on the bone scan. Prognosis is better when fewer than six skeletal metastases are found, and best when there are none. In the case presented herein, four representative bone scans are shown from a total of 16 obtained at approximately 6-month intervals over an 8-year period (Figs. 5 and 6). Progressive metastatic involvement of the skeleton occurs over many years, despite interval therapies which slow some lesions while new ones appear elsewhere. The interpretation is confounded by the patient s intermittent rib trauma. Generally, bone scans are not repeated sooner than 6 months during therapy, to avoid interpreting an osteoblastic healing response ( flare phenomenon) as worsening disease. However, the scans may be repeated as soon as 3 months if PSA levels or alkaline phosphatase levels are rising. Other imaging modalities such as monoclonal antibody imaging (Indium-111-ProstaScint) [14] and positron emission tomography scanning [15] may be helpful in individual situations in which standard modalities yield conflicting results. Table 1. Incidence of skeletal metastases by clinical stage 5%-10% Clinical stage I 10%-20% Clinical stage II 20%-49% Clinical stage III 60%-80% Clinical stage IV Table 2 Common sites of metastasis in the skeleton Pelvis: 73% Thoracic spine: 63% Lumbar spine: 62% Ribs: 61% Cervical spine: 51% Femur: 40% Skull: 28% Sacrum: 25% Humerus: 24% Figure 5. Radionuclide bone scans obtained in 1994 and 1996, following administration of Tc99m-methylene diphosphonate. A metastatic deposit is detected in the fourth lumbar vertebral body in 1994 (arrow), but diminishes in intensity by Figure 6. Radionuclide bone scans obtained in 1999 and 2000, following administration of Tc99m-methylene diphosphonate. Anterior rib lesions seen in 1999 may be due to innocuous trauma, typical in older individuals. In 2000, new lesions are identified in the spine and left sacral ala (arrows), but MRI showed them to be osteoporotic compression fractures. SURGICAL ASPECTS OF MANAGEMENT (DR. JOSEPH HARRYHILL) In the era of serum PSA with screening for early detection of prostate cancer, we are seeing far fewer cases of metastatic prostate cancer at presentation. One quandary that we face in surgical management of newly diagnosed prostate cancer is in defining treatment strategies for patients with high-risk disease who may ultimately progress to metastatic or hormone-refractory disease. What can be done to identify those patients at high risk for progression of disease, and what can we do to improve the prognosis in these patients since we have not had much of an impact with surgery as monotherapy?

5 187 Progressing Prostate Carcinoma Low-risk disease Treatment of low-risk disease Radical prostatectomy Radiation therapy Brachytherapy XRT Observation Figure 7. Treatment of low-risk prostate cancer. Brachytherapy When this patient originally presented, he was referred with an abnormal digital rectal examination and elevated serum PSA. Digital rectal examination was notable for a clinical stage B2 nodule according to both the Whitmore and Jewett classification. This is defined as a nodule greater than 2 cm involving one lobe of the prostate without extension into the seminal vesicle or periprostatic area. Ultrasound-guided biopsy of a hypoechoic lesion at the left prostatic apex yielded a Gleason sum 7 adenocarcinoma. When counseling patients regarding treatment options for newly diagnosed prostate cancer, the options reviewed are based on whether the patient has low-risk disease, high-risk High-risk disease: nodes negative Nodes negative disease with nodes negative, or high-risk disease with confirmed or suspected nodes positive. For a patient with lowrisk disease (PSA less than 10, Gleason 6 or less, and either a nonpalpable prostate lesion or a small lesion on digital rectal examination), the patient will likely do well with monotherapy (Fig. 7). In most cases the options include radical prostatectomy, EBRT, or prostate brachytherapy. For patients with limited-stage disease, radical prostatectomy and EBRT appear to give equivalent results, particularly with the development of newer technologies which allow higher doses of radiation to the tumor without damaging adjacent tissue [16-18]. Often the decision between surgery and radiation depends on patient s preference, age, and the presence of comorbid conditions. In many centers, radical prostatectomy is limited to the patients with localized disease who have better prognostic factors (such as lower Gleason score or lower PSA levels) [19]. In patients with localized disease who have poor prognostic patterns, radiation is often preferred [20]. There may be a limited role for considering cryosurgical prostate ablation. In an older patient with multiple medical problems or a limited life expectancy, observation may be appropriate with or without hormonal therapy. Amidst all the promising data regarding prostate brachytherapy for clinically localized disease [21], there are data to suggest that high-grade lesions (Gleason greater than or equal to 7) do not respond as well to brachytherapy when compared to either EBRT or radical prostatectomy [21, 22]. This patient actually falls into the category of presenting with high-risk disease with nodes negative at the time of pelvic lymphadenectomy (Fig. 8). In those patients with high-risk Radical Radical prostatectomy prostatectomy Radiation Radiation therapy therapy Cryosurgical prostate ablation External External beam beam radiation radiation Brachytherapy Brachytherapy with with XRT XRT boost boost Consider adjuvant hormonal therapy Figure 8. Treatment of high-risk prostate cancer with negative nodes.

6 Haut, Harryhill, Rosenstock et al. 188 High-risk disease: nodes positive Nodes positive Radical Radical prostatectomy prostatectomy + hormonal (Mayo series) therapy XRT XRT + + hormal hormal therapy therapy Immediate Immediate hormonal hormonal therapy therapy Delayed Delayed hormonal hormonal therapy therapy Orchiectomy LHRH Orchiectomy analogue LHRH LHRH + + antiandrogen antiandrogen Figure 9. Treatment of high-risk prostate cancer with positive nodes. disease and negative lymph nodes, appropriate therapy may include radical prostatectomy, EBRT, or cryosurgery [22, 23]. It is becoming clear that we need to consider the role for adjuvant or neoadjuvant therapy in these patients [24-26]. Several series have looked at the feasibility and efficacy of pretreating patients with hormone therapy prior to radical prostatectomy, and results are mixed. Evidence indicates that the prostate can be downsized and in some cases downstaging of the prostate cancer occurs [24, 25]. This patient had positive margins at the time of radical prostatectomy. The question that has not been conclusively answered in the study of neoadjuvant hormonal therapy and surgery is whether there is improvement in disease-specific or overall survival. With EBRT there may be an advantage in patients who are pretreated with hormonal therapy. The more significant problem arises in the patient with high-risk disease with nodes positive (Fig. 9). These are patients who already have systemic disease. Clearly this is a patient population in need of multimodal therapy. There has been a renewed interest in chemotherapy and hormonal regimens [26-28]. Rather than chemotherapy as salvage, researchers are beginning to rethink a paradigm and look at chemotherapy up front in patients with high-risk disease rather than waiting until they fail extensively. Radical prostatectomy may be useful to consider in selected patients with node-positive disease, especially in younger patients. Surgery provides local control and reduces the risk of later problems associated with bleeding and bladder outlet obstruction. In addition, immediate androgen ablation following radical prostatectomy in patients with node-positive disease is strongly associated with improved survival and reduced risk of tumor recurrence, as reported recently by Messing et al. [29]. Combination radiation and hormonal therapy is an important option to discuss. As pointed out in the Radiation Therapy Oncology Group (RTOG) trial comparing EBRT plus immediate androgen ablation versus EBRT alone, there is improved progression-free survival in patients treated with combination therapy at 5-year follow-up [30]. Hormonal therapy alone would be a consideration in a patient who is not a suitable candidate for aggressive treatment. Keep in mind that the urologist can be helpful in the management of patients with metastatic or advanced disease. Bilateral orchiectomy remains an excellent alternative in the patient who requires androgen ablation, and enjoys some advantages in both convenience and economy when compared to luteinizing-hormone-releasing hormone (LHRH) agonist therapy. If you compare the cost of a patient undergoing orchiectomy to the expense of hormonal therapy with LHRH agonist injections, the cost for medical castration is approximately twice that of orchiectomy after 1 year [31]. The surgeon also has a role in managing problems of bladder outlet obstruction in patients with advanced prostate cancer, and channel TURP (transurethral prostatectomy) to relieve bladder outlet obstruction is indicated in selected patients. RADIATION ONCOLOGY (DR. JEFFREY ROSENSTOCK) I am going to confine my comments to the use of radiation as salvage therapy. Management of the patient with biochemical failure after radical prostatectomy is controversial and complex. The first issue is definition of failure persistent elevation of PSA post surgery, a rising PSA following an undetectable nadir, high-risk findings at time of surgery, or biopsy proof of recurrence. Whether these factors portend metastatic disease or just indicate local failure has yet to be clearly defined. The clinical experience varies widely. In institutions with high surgical volume and very precise patient selection criteria, the rate of elevated PSA development within 5 years of surgery is approximately 10% [32, 33]. In institutions with less stringent selection criteria for surgery, there is a higher incidence of positive margins or

7 189 Progressing Prostate Carcinoma vesicle involvement found at surgery and a higher rate of rising PSA within 5 years following prostatectomy (biochemical failure). Do such high-risk factors inevitably lead to local and systemic failure and does adjuvant therapy, especially with radiation, change the natural history? Do you need biopsy confirmation of local failure or is simply a rising PSA enough to indicate the need for radiation therapy? Finally, what are the risks of radiation therapy post radical prostatectomy? Data that answer these questions are being accumulated and are slowly maturing. These data must be adapted to a population which is often elderly and may have significant comorbid processes. Some efforts have been made to use preoperative PSA, clinical stage, and Gleason grade in the biopsy specimens to predict pathologic stage [34] and prostate cancer recurrence [35]. The risk factors for biochemical failure include: T3 tumors with positive margins, involvement of seminal vesicles, or Gleason score greater than 7. Each of these factors gives an approximate 50% chance of rising PSA by 5 years, in the absence of adjuvant therapy. But, surprisingly, even positive margins do not give a 100% chance of failure defined by rising PSA alone [36]. The radiation therapy literature shows that treating high-risk patients whose PSA had started to rise but was less than 1 ng/ml resulted in a long-term PSA control rate of as high as 75%. Of course not all of these patients would have necessarily shown clinical progression despite the persistence of an elevated PSA or the presence of a rising PSA. If one limits the use of salvage radiation therapy to patients with higher PSA levels or biopsy confirmation of local recurrence in the face of a negative bone scan, then the biochemical long-term control is less than 40% [37]. The toxicity from limited fields of radiation to the prostate bed of patients post radical prostatectomy has been remarkably low. Acute toxicity of mild to moderate diarrhea and cystitis is common but resolves quickly. Long-term incontinence of bowel and bladder in patients who have good control post prostatectomy has been less than 3%. In contrast, impotence in those patients who had potency post surgery has been greater than 40%. Bowel damage requiring colostomy has been reported only rarely. A recent survey of the urologic community showed that biochemical failure post radical prostatectomy is usually followed by observation, and only biopsy-confirmed local recurrences are treated with radiation therapy [38]. In contrast, the consensus statement from the American Society for Therapeutic Radiology and Oncology recommends adjuvant radiation therapy without necessarily having biopsy proof of local failure in select high-risk patients with rising PSA, with therapy being instituted when PSA levels are under 1.5 ng/ml [39]. A consistent approach will require prospective randomized studies to determine the optimum criteria for radiation in patients who have had radical prostatectomy. Table 3. Hormonal therapy for advanced prostate cancer Monotherapy Bilateral orchiectomy Estrogen therapy LHRH (GnRH) agonists (leuprolide acetate or goserelin or buserelin) LHRH (GnRH) antagonists (abarelix) Progestational agents (megestrol acetate or cyproterone acetate) Nonsteroidal antiandrogens (flutamide, bicalutamide, nilutamide) Adrenal enzyme synthesis inhibitors (ketoconazole, aminoglutethimide) Combined androgen blockade Intermittent androgen ablation Second-line hormone treatment e.g. High dose bicalutamide in patients failing flutamide MEDICAL ONCOLOGY (DR. MICHAEL HAUT) The role of systemic therapy in patients with prostate carcinoma has undergone evolution in recent years, with the development of multiple choices for hormonal therapy and the more recent development of effective chemotherapy. In addition, the development of predictive models for disease relapse following initial monotherapy (particularly surgery) has raised the possibility that neoadjuvant or adjuvant therapy may alter the course of a patient s disease. In my discussion, I will focus on three aspects of systemic therapy. First, I will briefly address the use of hormone therapy in metastatic disease. Then, I will discuss chemotherapy and other modalities of therapy for hormone-refractory disease. Finally, I will touch on the use of adjuvant and neoadjuvant systemic therapy for poor prognosis locoregional disease, which has been addressed by Dr. Harryhill. Table 3 lists various hormonal manipulations used in treating systemic disease in patients with prostate carcinoma. Bilateral orchiectomy is still done in some patients, but has been replaced in many patients by medical castration, either with an LHRH (GnRH) agonist (leuprolide or goserelin or buserelin) alone, or with combined androgen blockade, using an LHRH (GnRH) agonist and an antiandrogen such as flutamide or bicalutamide. Patients who are responding to medical castration, but cannot tolerate the LHRH agonists, may respond to intermittent androgen ablation. Ketoconazole has been used in some patients progressing on hormonal therapy, as has high-dose bicalutamide. Recently, a new LHRH (GnRH) antagonist (Abarelix) has been developed which does not cause an initial stimulation of LH and therefore does not cause initial elevation of testosterone or dehydrotestosterone [40]. A major problem in management of prostate cancer is how to treat patients with systemic progression after hormonal

8 Haut, Harryhill, Rosenstock et al. 190 Table 4. Assessment of response to therapy in metastatic prostate cancer [41] Overall survival Need to stratify patients to eliminate bias. Decrease in measurable soft tissue disease Only about 20% of patients with metastatic prostate cancer have measurable soft tissue disease. Sites predominantly involved are pelvic and retroperitoneal lymph nodes, lung and liver. Response of bony disease Flare phenomenon Mixed responses Post-therapy decrease in serum PSA 50% decrease at 8 weeks Suramin can decrease expression of PSA messenger RNA without causing cell death. Successful differentiation therapy with retinoids can produce an increase in PSA prior to a decline, due to an increase in the amount of PSA produced by a differentiated as opposed to an undifferentiated cell. Quality of life therapy. A particularly difficult problem in developing systemic chemotherapy regimens for hormone-refractory prostate cancer is the difficulty of assessing response to a given therapy [41]. Table 4 outlines several variables which are currently used to assess response to therapy in patients with prostate carcinoma. Overall survival is an important variable. When determining the effect of a given regimen on survival, it is necessary to stratify patients to eliminate bias. Measuring response to therapy by examining decrease in soft tissue disease demonstrated on CT scan is objective, but only about 20% of patients with metastatic prostate cancer have measurable soft tissue disease. Response of bony disease is not as easy to interpret because bone scans can take a long time to show improvement when a treatment is working because of the flare phenomenon occurring in responding patients and because some patients have mixed responses. Post-therapy decrease in serum PSA has been a valuable measure of clinical response. A response is defined as a decrease of 50% or more in PSA level in 8 weeks after starting therapy. However, one must be careful in interpreting a falling PSA as improvement. Suramin can cause decreased expression of PSA messenger RNA without cancer cell death [42], and successful differentiation therapy with retinoids can produce an increase in PSA prior to a decline, due to an increase in the amount of PSA produced by a differentiated as opposed to an undifferentiated cell [43]. Quality of life (measured by diminished use of pain medication and answers to questionnaires) has been useful in assessing response to therapy. Table 5 lists a number of the major chemotherapeutic regimens that have been examined as treatment for hormonerefractory prostate carcinoma. The two types of regimens listed at the top, mitoxantrone plus a glucocorticoid or estramustine plus a taxane, have been the most frequently used. In Table 6 the results of two studies using mitoxantrone and a glucocorticoid are shown. In the first one [44], 38% of the mitoxantrone plus prednisone group had a palliative response versus 21% of the group receiving prednisone alone. It is important to note that there was a response in the group receiving prednisone alone, even though the group receiving mitoxantrone and prednisone had a higher response rate. There was no significant difference in median survival between the two groups. Although PSA was not a primary end point for this study, reanalysis of the PSA data showed that 39% of the patients with available PSA data on the mitoxantrone arm had evidence of response by this criteria. In the second study [45], a Cancer and Acute Leukemia Group B study of 242 patients (CALGB-9182), there was improvement in pain control in the chemotherapy arm as well as a delay in time-to-treatment failure and disease progression in the chemotherapy arm, but no difference in overall survival between the two arms. Table 5. Chemotherapy for hormone refractory prostate cancer Mitoxantrone plus glucocorticoid a Estramustine plus paclitaxel (taxol) or docetaxol (taxotere) a Estramustine plus vinblastine Estramustine plus vinorelbine Estramustine plus etoposide Estramustine, etoposide, and paclitaxel Doxorubicin Cytoxan a Most frequently used. Table 6. Mitoxantrone plus glucocorticoid Randomized phase III comparison of mitoxantrane (12 mg/m 2 every 3 weeks) plus prednisone (5 mg bid) versus prednisone alone (80 patients) [44]. 38% of mitoxantrone plus prednisone group had palliative response versus 21% of prednisone group. PSA was not a primary end point for this study, but a reanalysis of the PSA data showed that 39% of the patients with available PSA data on the mitoxantrone arm had evidence of response by this criterion. No significant difference in median survival between the two groups. Cancer and Acute Leukemia Group B study of mitoxantrane plus hydrocortisone versus hydrocortisone alone (242 patients) [45]. Improvement in pain control in chemotherapy arm. Delay in time to treatment failure and disease progression in chemotherapy arm. No difference in overall survival between the two arms.

9 191 Progressing Prostate Carcinoma Table 7. Mechanism of action of microtubule inhibitors and of estramustine [46] The anti-apoptotic protein, Bc1-2, is expressed in approximately 65% of androgen independent human prostate cancer specimens and in approximately 25% of hormonally untreated specimens. Bc1-2 appears to impart both androgen-independent growth and chemoresistance. Antitubulin chemotherapeutic agents, such as taxanes and vinca alkaloids, inactivate Bc1-2 at the G 2 -M phase of the cell cycle by phosphorylation. Estramustine acts by binding to microtubules and the nuclear matrix. Table 8. Estramustine plus a taxane Estramustine plus paclitaxel (taxol) Estramustine (600 mg/m 2 /day continuously) plus paclitaxel (120 mg/m 2 by 96 hour infusion on days 1 to 4 every 21 days) [47]. Objective response rate = 45% (4 of 9 patients with measurable soft tissue disease). PSA response = 53% (17 of 32 patients with elevated pre-treatment PSA level). Estramustine plus docetaxol (taxotere) Estramustine (10 mg/kg/day p.o. days 1-5) plus taxotere (60-80 mg/m 2 i.v. on day 2) every 21 days [48]. 28% (5 of 18 patients) with measurable disease had partial response. 63% (21 of 33) had 50% or greater decline in serum PSA. 53% (8 of 15 patients) were able to discontinue their pain medications. Microtubule inhibitors, such as the taxanes, in combination with estramustine, have also been shown to be effective. Bcl-2, an anti-apoptotic protein, appears to impart both androgen-independent growth and chemoresistance to prostate cancer cells. Antitubulin chemotherapeutic agents such as taxanes and vinca alkaloids inactivate Bcl-2 at the G 2 -M phase of the cell cycle by phosphorylation. Estramustine, which consists of nornitrogen mustard bound to estradiol, was initially developed to deliver the nornitrogen mustard to estrogen receptor-positive prostate tumor cells. It was found to work primarily by inhibiting microtubules synergistically with taxanes or vinca alkaloids. Table 7 outlines the mechanism of microtubular inhibitors and estramustine [46]. Table 8 shows the results of two major studies of estramustine and taxanes. Numerous studies have examined these two agents. Oral estramustine plus paclitaxel (Taxol) by 96-h infusion produced an objective response of 45% (four of nine patients with measurable soft tissue disease) and a PSA response of 53% (17 of 32 patients with elevated pretreatment PSA levels) [47]. Estramustine plus docetaxel (Taxotere) produced an objective response rate of 28% (5 of 18 patients with measurable soft tissue disease) and a PSA response of 63% Table 9. SWOG (Southwest Oncology Group) 9916 ARM 1 12 mg/m 2 mitoxantrone (escalated to 14 mg/m 2 if no grade 3 or 4 toxicities are observed in cycle 1) on day one combined with 5 mg prednisone orally twice a day, days 1-21, every 3 weeks. ARM mg estramustine orally 3 times a day for days 1-5, 60 mg/m 2 docetaxel on day 2 (escalated to 70 mg/m 2 if no grade 3 or 4 toxicities are observed in cycle 1), and 20 mg decadron given at midnight, 6 a.m. and just before docetaxel administration. Repeat every 3 weeks. Table 10. Estramustine plus other agents Multicenter trial of estramustine and vinblastine versus vinblastine alone. [53] Total patients = 193 Estramustine and vinblastine 20% had decrease in measurable soft tissue disease 25% had a PSA response Vinblastine alone 6% had decrease in measurable soft tissue disease 3% had a PSA response Estramustine plus vinorelbine [54] 0% soft tissue response (0 of 5 patients with measurable disease) 38% PSA response (9 of 24 patients) Estramustine plus etoposide [55] 50% soft tissue response (9 of 18 patients) 52% PSA response (32 of 42 patients) Estramustine, etoposide, and paclitaxel [56] Total patients = 40 45% soft tissue response (10 of 22 patients) 65% PSA response (26 of 40 patients) (21 of 33 patients) [48]. Unlike paclitaxel, docetaxel has significant single-agent activity, with a PSA response rate of 46% (16 of 35 patients) [49]. Currently, an intergroup study (SWOG 9916) initiated by the Southwest Oncology Group is under way, comparing mitoxantrone and prednisone with estramustine and docetaxel (Table 9). Prior to examination of the taxanes with estramustine, vinblastine was examined. In three phase II studies, totaling 92 patients, PSA responses were seen in 50% (44 of 88 patients), and decreases in measurable disease were seen in 24% (6 of 25 patients) [50-52]. A particularly important study of these two drugs was a randomized trial of vinblastine plus estramustine versus vinblastine alone [53]. This study (Table 10) showed no significant difference in overall survival between the two-drug and one-drug regimens, but did show significant soft tissue and PSA response with the two-drug regimen. This study, which was interpreted to show that estramustine added activity to vinblastine, was important because it addressed the question

10 Haut, Harryhill, Rosenstock et al. 192 Table 11. Older regimens Doxorubicin Weekly doxorubicin (20 mg/m 2 /wk) [57] Minimal objective response but significant palliative effect Doxorubicin in combination with other agents such as ketoconazole Some effectiveness, but significant toxicity Cyclophosphamide Standard dose i.v., single agent or in combination Minimal activity Oral, over an extended period Objective response rate of 20%, with 60% experiencing subjective improvement High dose cyclophosphamide Significant activity, but no evidence of improvement of response rate or survival about whether estramustine was Table 12. Experimental approaches critical to combinations of estramustine plus a microtubule inhibi- A. Herceptin B. Differentiation therapy tor. A study of vinorelbine, another Retinoids microtubule inhibitor, and estramustine [54] showed no soft tis- Vitamin D derivatives Phenylbutarate sue response, and a 38% PSA C. Cytostatic agents response. Monoterpenes Estramustine has also been Growth factor inhibitor examined in combination with etoposide, a topoisomerase II D. Tumor vaccines inhibitor [55]. This combination E. Gene therapy shows a 50% tissue response (9 of 18 patients) and a 52% PSA response (22 of 42 patients). Some work has been done on three-drug regimens. In one study examining estramustine, etoposide, and paclitaxel, 45% (10 of 22 patients) had a measurable disease response and 65% (26 of 40 patients) had a PSA response [56]. Before mitoxantrone/glucocorticoid and estramustine/ microtubule inhibitor-based regimens were developed, a number of other agents were examined in detail. Some of these are listed in Table 11. For a number of years, weekly doxorubicin was used for clinical palliation of hormone-refractory prostate cancer [57]. Doxorubicin has been used in conjunction with other agents as well. One study utilized weekly doxorubicin in combination with daily ketoconazole [58]. In this study 55% of patients (21 of 38) showed a PSA response, and 58% (7 of 12 patients) showed a soft tissue response. This study, and a subsequent study alternating ketoconazole and doxorubicin with estramustine, which had a similar good response, demonstrated significant cardiac, infectious, and cutaneous toxicity. Although cyclophosphamide showed minimal activity at standard intravenous doses, low-dose daily oral cyclophosphamide has been demonstrated to have a modest PSA response and a significant symptomatic response. A number of agents that have been examined have been shown to have minimal value in treating hormone-refractory prostate carcinoma. Camptothecin analogues such as topotecan, irinotecan, and 9-amino camptothecin have been shown to be ineffective. Although cyclophosphamide has been shown to have a modest response, ifosfamide and melphalan have not been shown to be effective. Matrix metalloproteinase inhibitors, such as AG3340, also have been shown to be ineffective. A number of experimental approaches have been tried (Table 12). Overexpression of Her-2/neu has been shown to be associated with androgen independence and drug resistance in prostate cancer cells. At present the data are not clear about the relevance of overexpression of Her-2/neu in specific groups of patients, but there is considerable interest in the use of herceptin in prostate carcinoma, particularly in view of its synergistic effects with the taxanes. Differentiating agents, including retinoids, phenylbutyrate, and vitamin D analogues are being examined both in vitro and in vivo. The value of vitamin D analogues has been limited by hypercalcemia, but nonhypercalcemic analogues have been developed and are being examined [59]. Growth factor blockade using a combination of epidermal growth factor receptor monoclonal antibody and doxorubicin was examined [60], and showed disease stabilization. Tumor vaccines are being investigated in a number of centers, and gene therapy approaches are being used to induce immunity [61] or kill tumor cells [62]. The availability of a number of effective hormonal and chemotherapeutic agents which are effective against prostate carcinoma enables us to intervene in these patients who have a high likelihood of recurrence. As noted by Dr. Harryhill and Dr. Rosenstock in their presentations, there are a number of predictive tools to determine which patients are most likely to develop recurrent disease [34, 35]. A number of studies in recent years have examined the possibility of delaying relapse with adjuvant therapy. In patients who have undergone radical prostatectomy who are found to have poor prognostic indicators, adjuvant radiation therapy has been used [63-65]. Adjuvant hormonal therapy has been examined by many investigators, and is widely used following surgery [29] or radiation [26, 30, 66, 67] in patients node positive or with otherwise poor prognosis disease. Adjuvant chemotherapy is being examined as well, but its benefit is unproven at present. Two studies conducted by the National Prostate Cancer Project after either radical prostatectomy or radiation therapy showed increased progression-free survival in patients treated with estramustine versus those treated with cyclophosphamide or observation alone [68].

11 193 Progressing Prostate Carcinoma Neoadjuvant therapy has been examined in patients treated with primary radiotherapy [24, 69, 70] and those treated with radical prostatectomy [24, 25]. Several studies [24, 69, 70], including one by RTOG (RTOG-8610) [69], showed improvement in local control and disease-free survival in patients treated with neoadjuvant hormonal therapy followed by radiation versus treatment with radiotherapy alone [24, 70]. In patients treated with surgery as the primary therapy, neoadjuvant hormone therapy decreased the incidence of positive surgical margins but did not result in increased disease-free or overall survival [24, 25]. CONCLUSIONS A number of features of this patient s clinical course demonstrate clinical management points. His positive surgical margins and the rate of rise of his PSA following surgery made it likely that he would relapse. When he did relapse, he did first locally, and this local recurrence was treated with radiation therapy. When he recurred systemically, his disease was controlled with hormonal therapy. When he became refractory to hormonal therapy, he was placed on a chemotherapeutic regimen. The pathologist and radiologist offer considerable help in determining which therapy to initiate at the time of presentation. The pathologist determines the histologic aggressiveness of the tumor using the Gleason rating pattern. This morphologic system is based on architectural pattern in two separate areas of tumor. On examination of the tumor in the resection specimen from patients who have undergone radical prostatectomy, the pathologist can evaluate for extracapsular invasion and seminal vesicle involvement, both poor prognostic signs. The radiologist has a number of tools, including CT scans, MRI and radionuclide scans, to determine the anatomic extent of disease at presentation. Based on the data obtained by the above methods, the clinicians involved in the patient s care can make a rational decision about initial therapy. A number of predictive techniques, utilizing data obtained prior to initial therapy, can help to determine which patients will do well with monotherapy, and which ones will require additional treatment at the time of initial therapy. Surgical approach to patients with newly diagnosed prostatic carcinoma is based on whether the patient has low-risk disease, high-risk disease with nodes negative, or high-risk disease with confirmed or suspected node positivity. Patients with lowrisk disease will do well with monotherapy-radical prostatectomy, EBRT, prostate brachytherapy, or in some cases cryosurgical prostatic ablation. In patients who have high-risk disease and negative lymph nodes, therapy could include radical prostatectomy, EBRT, or cryosurgery. Neoadjuvant or adjuvant therapy may be useful in these patients. Patients with high-risk disease with lymph node positivity require multimodal therapy. In some younger patients, radical prostatectomy may be useful to consider in the presence of node-positive disease, in addition to hormonal therapy and chemotherapy. Adjuvant and neoadjuvant therapy regimens have been investigated in an attempt to change the clinical course of patients with a high-risk of recurrence following definitive monotherapy. Adjuvant radiation therapy has been shown to be effective in patients with poor prognosis locoregional disease. Adjuvant hormonal therapy has been demonstrated in many studies to improve survival in patients with a high likelihood of recurrence following surgery or radiation. Adjuvant chemotherapy has also been examined, but the results so far have been inconclusive. Neoadjuvant therapy has been shown in some studies to increase local control and disease-free survival in patients treated with radiation therapy. In patients treated with surgery, neoadjuvant hormonal therapy decreased the incidence of positive surgical margins, but failed to increase disease-free or overall survival. Treatment for patients who progress after initial therapy can involve radiotherapy, hormonal therapy, or chemotherapy. Radiation therapy can be used as salvage therapy in a patient with biochemical failure after radical prostatectomy. The radiation therapy literature shows that treating high-risk patients whose PSA has started to rise but is below 1 ng/ml results in a long-term PSA control rate as high as 75%. If one limits the use of salvage radiation therapy to patients with higher PSA levels or biopsy-confirmed local recurrence in the face of a negative bone scan, then the biochemical long-term control is less than 40%. The toxicity from limited field radiation to the prostatic bed of patients who have had radical prostatectomy is low, with long-term incontinence of bowel or bladder in patients who had continence after prostatectomy less than 3%; however, 40% of those potent post-surgery will become impotent after salvage radiation therapy. Hormonal therapy for metastatic prostate carcinoma includes bilateral orchiectomy and medical castration either with LHRH agonists alone or with combined androgen blockade using an LHRH agonist and antiandrogen. Ketoconazole has been used in some prostate patients progressing on hormonal therapy, as has high-dose bicalutamide. Patients who develop systemic progression after hormonal therapy may be considered for chemotherapy. 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