Case Reports on Prostate Cancer

TREATMENT OF SYMPTOMATIC PROSTATE CANCER PATIENTS Case Reports on Prostate Cancer [Rev Urol. 2004;6(suppl 7):S39-S45] © 2004 MedReviews, LLC Key words: Adenocarcinoma • Prostate-specific antigen • Gleason score • Androgen deprivation • Radical prostatectomy • Spinal cord compression • Ketoconazole • Antiandrogens • Abarelix • Gonadotropin-releasing hormone • Nomograms • Radiotherapy • Mitoxantrone • Prednisone Case 1: Adenocarcinoma of the Prostate 66-year-old man was shown to have a prostate-specific antigen (PSA) level of 8 ng/mL in a routine evaluation. His physical exam was normal and the digital rectal examination revealed a slightly enlarged prostate. Prostatic biopsy revealed a Gleason score 7 (4 + 3) adenocarcinoma in 6 of 12 specimens. His past medical history was unremarkable. Laboratory data showed the following: hemoglobin level 15 g/mL, hematocrit 43%, white blood cell count (WBC) 7,500 mm3, normal differential, platelets 250,000, blood urea nitrogen 15, creatinine 1.0, and normal alkaline phosphatase and liver function tests. Chest X-ray, bone scan, and abdominal CT scan were negative. He underwent a radical retropubic prostatectomy and the final pathology A VOL. 6 SUPPL. 7 2004 REVIEWS IN UROLOGY S39 Case Reports continued revealed a Gleason score 8 (4 + 4) adenocarcinoma involving approximately 60% of the gland, established capsule penetration, and right seminal vesicle involvement. In addition, 1 of 5 lymph nodes on the right side demonstrate metastatic adenocarcinoma. Three months after surgery his PSA is undetectable. ical models and nomograms that allow for postoperative prediction of biochemical recurrence and the identification of defined risk groups using the known prognostic parameters.1,5-7 There is no standard approach for patients at high risk for relapse following local treatment. Hormonal Diagnosis pT3, N+, Mx, Gleason score 8 (4 + 4) adenocarcinoma of the prostate. The use of androgen deprivation in the adjuvant setting for patients with stage N+ (D1) disease remains controversial. Treatment Options Observation followed by deferred hormonal therapy, immediate hormonal therapy, enrollment in a clinical trial. treatment remains the most effective systemic treatment for metastatic prostate cancer. However, it is primarily palliative and the evidence of a survival benefit remains controversial.8 The use of androgen deprivation in the adjuvant setting for patients with stage N+ (D1) disease also remains controversial.9 The evidence of a survival benefit of adjuvant androgen deprivation is limited primarily to a relatively small randomized study and requires further confirmation prior to standard use.10 At the present time, the National Cancer Institute's intergroup study 9921 represents an alternative that practicing physicians and patients should explore vigorously. In this study, high-risk patients following Discussion The management of patients with high-risk, early-stage prostate cancer represents a major challenge to all disciplines involved in the treatment of this common malignant neoplasm. Among the basic requirements allowing for early intervention in highrisk patients are a definition of the disease's natural history, including identification of key prognostic factors, and the availability of active systemic therapeutic modalities for patients with advanced disease. The relative risk for development of MRI of the spine revealed a metastatic lesion at the level of T10, showing infiltration of the entire vertebral body marrow space, which was suspicious for metastasis. biochemical recurrence is dependent on various preoperative and postoperative clinical and pathologic factors. Multivariate analyses indicate that the most significant independent predictors are preoperative PSA, pathologic T stage, and final Gleason score (based on the prostatectomy specimen).1-5 Four independent groups of investigators developed mathemat- S40 VOL. 6 SUPPL. 7 2004 radical prostatectomy are randomized to receive 2 years of androgen deprivation versus androgen deprivation and 6 months of the combination of mitoxantrone and prednisone.11 Given the recent demonstration of a survival benefit of docetaxel combinations in patients with hormone refractory disease, it is likely that additional studies will soon become REVIEWS IN UROLOGY available for these patients. [Mario A. Eisenberger, MD] Case 2: Adenocarcinoma of the Prostate A 68-year-old retired chef initially complained of frequency of micturition, urinary urgency, and hesitancy associated with a weak stream. Over the past several weeks, he has reported a few episodes of hematuria and incontinence. In addition to his urologic symptoms, the patient complained of low-grade, constant back pain and bouts of constipation. A digital rectal examination revealed the patient has an enlarged prostate gland with several palpably discreet nodules. His past medical history was unremarkable. Laboratory Studies The patient had a prostate-specific antigen (PSA) level of 95 ng/mL (range: 0.0-4.0 ng/mL), while a similar determination 6 years earlier showed a PSA of 1.5 ng/mL. His hemoglobin was 15 g/dL (range: 13.2-17.1 g/dL), hematocrit 43% (range: 38.5-50%), white blood cell 7,500/mm3, normal differential, platelets 250,000/mm3, blood urea nitrogen 15 mg/dL (normal range: 7-30 mg/dL), and creatinine level 1.0 mg/dL (range: 0.5-1.4 mg/dL). Alkaline phosphatase and liver function tests were all within normal range. Imaging Studies A transrectal ultrasonographyguided biopsy was performed. During the biopsy procedure, the ultrasound revealed many hypoechoic or echopenic areas within the homogeneous parenchyma of the gland (Figure 1). MRI of the spine revealed Case Reports Figure 1. Sonogram of the patient’s prostate gland. Arrows indicate hypoechoic areas within the homogenous parenchyma, demonstrating widespread neoplastic disease, which has metastasized beyond the capsule. a metastatic lesion at the level of T10, showing infiltration of the entire vertebral body marrow space, which was suggestive of metastasis (Figure 2). There was no evidence of cord compression; however, there was signal activity in proximity to the corresponding nerve root. Radionuclide scintigraphy demonstrated several areas along the spine suggestive of metastatic bone disease, which were Figure 2. MRI of spine revealing metastatic infiltration of entire T10 vertebral body marrow space. consistent with evidence derived from MRI studies (Figure 3). Chest, abdominal, and pelvic CT scans demonstrated no evidence of nodal or visceral metastasis; however, the prostate was enlarged and irregular with extensive deformity of the bladder neck. Staging In the Tumor, Nodes, Metastases Figure 3. Radionuclide bone scan showing metastatic bone disease secondary to prostatic adenocarcinoma. Osseous sites of increased uptake can be identified in the spine (T1 to T12) and ribs. staging system, the tumor had extended bilaterally through the prostatic capsule (T3b), and metastasis was found in bone (M1b). The patient was staged as stage D2 with extensive local disease. Biopsy Results Histologic evaluation of the biopsy specimens revealed a Gleason score of 8 (4 + 4) and adenocarcinoma in 7 Figure 4. Biopsy specimen (hematoxylin and eosin 1000X) reveals adenocarcinoma of the prostate gland with a Gleason score 8 (4 + 4) representing 60% of the tissue sample. This neoplasm was characterized by well-defined acini arranged in a backto-back formation. Cells showed prominent nucleoli and absence of a basal layer. VOL. 6 SUPPL. 7 2004 REVIEWS IN UROLOGY S41 Case Reports continued of 12 multiple cores, representing 60% of the biopsied material (Figure 4). Diagnosis Based upon prostate biopsy evaluation and ultrasound images, radionuclide scintigraphy, and MRI studies, a diagnosis was made of advanced prostatic adenocarcinoma with metastases to the bone. Treatment Options In view of the advanced stage of the disease and evidence of distant metastasis, the primary treatment modality for this patient was systemic therapy. and relief of obstruction, a course of palliative external beam radiation was administered. A total of 40 treatments over an 8-week period consisted of 3dimensional conformal radiation therapy, which delivered a total 6570 Gy dose of radiation to the prostate. Treatment of Bone Metastases Abarelix produced a rapid decline of the serum PSA to < 0.1 ng/mL after 3 months of treatment. This was associated with major improvements in pain. External beam radiation to the involved vertebral body was subsequently delivered to enhance local control and to minimize the possibility After a 3-month treatment with abarelix, the patient experienced a significant improvement of his urological symptoms. The pattern of metastatic disease, that is, extensive local involvement and likely extension into the bladder, as well as the virtual replacement of a vertebral body with disease in close anatomic proximity to the nerve root, suggested that in addition to the standard systemic approach, local palliative measures should be considered. Importantly, the constellation of signs and symptoms of this patient’s disease underscored the critical need to select a systemic treatment that produced a rapid decline of serum testosterone and consequently allowed prompt control of the disease. He was, therefore, treated with abarelix,12 a gonadotropin-releasing hormone (GnRH) antagonist. External Beam Radiation Therapy The role of radiation therapy in the setting of this patient’s disease was primarily palliative and focused on the control of local obstructive problems. After a 3-month treatment with abarelix, the patient experienced a significant improvement of his urological symptoms. To further improve local control S42 VOL. 6 SUPPL. 7 2004 of future neurological complications resulting from spinal cord or nerveroot compression. To further improve the management of bone metastasis, the patient was initiated on bisphosphonate treatments with intravenous infusions of zoledronic acid. Follow-Up Follow-up at 6 months showed a healthy-looking patient with PSA level < 0.1 ng/mL. Long-term gonadal suppression with abarelix was treatment of advanced cancer of the prostate has been standard treatment for many years.13 The role for local radiation therapy in patients with distant metastasis is primarily palliative. In this case, it was elected to proceed with external beam radiation to metastatic sites primarily to increase local control of severely involved sites associated with major symptoms and impending serious life- and functionally threatening complications. Specifically, there was evidence of significant anatomic bladder-outlet obstruction and potentially impending neurological compromise due to local extension of disease to the radicular space. Furthermore, the patient demonstrated significant symptoms associated with these involved metastatic sites.13,14 Androgen ablative therapy with abarelix was shown to be highly effective in reducing the PSA to < 0.1 ng/mL in a short period of time. The use of a GnRH antagonist (abarelix) in this setting was critical in view of the severity of symptoms and need for rapid therapeutic effects. In addition, the flare phenomenon (reported in 10% to 30% of patients treated with luteinizing hormone-releasing hormone agonists) is avoided with abarelix, which is a major factor in the selection of GnRH antagonists as the initial treatment approach.13,15 The use of androgen ablation in the treatment of advanced prostate cancer has been the standard treatment for many years. planned and the patient was continued with serial physical exams, routine blood evaluations, including serum PSA determinations at regular intervals (every 2 to 3 months), and radiological assessments every 6 to 12 months or as clinically indicated. Discussion The use of androgen ablation in the REVIEWS IN UROLOGY The prognosis for this patient is poor due to the extensive degree of metastatic bone involvement.13 Data derived from large prospective randomized trials indicate that the median time to progression with conventional forms of androgen ablation approaches ranges between 12 to 18 months and the median survival is around 30 to 36 months.13,15 Case Reports The main issue centers around the development of hormone resistance. Evolving data with new chemotherapeutic approaches suggest that nonhormonal treatment plays a significant role in the treatment of patients with hormone-resistant prostate cancer and may be a major addition to hormonal treatment in the initial management of patients with metastatic disease. [Mario A. Eisenberger, MD] Case 3: Spinal Cord Compression A 79-year-old retired colonel presents to the clinic with lower back pain. His status is postradical prostatectomy in currence of prostate cancer. Although technically it would be desirable to obtain a tissue diagnosis, the clinical presentation makes it highly unlikely that a second primary such as lymphoma, lung, or colon cancer is causal. Control of the patient’s pain and the impending spinal cord compression are the most important factors to consider in management. Treatment Options Frank spinal cord compression is a medical emergency. Repeating a more careful neurologic examination might show symmetric loss in The recent FDA approval of a GnRH antagonist, abarelix, offers a new option for the management of prostate cancer patients at risk for spinal cord compression. 1992 for a Gleason 7, T2B, margin positive, node negative prostate cancer. He received postoperative radiation therapy to the prostate bed and his prostate-specific antigen (PSA) level was undetectable on annual visits until last year. In the past 12 months, PSA has climbed from 1.2 to a present value of 53.4. Physical examination reveals an empty rectal fossa and mild tenderness to percussion over the L2-3 region. His neurologic examination is negative. A bone scan reveals multiple rib and spine lesions including the tender area over the lumbar spine. Routine radiographs document sclerotic lesions matching many of the radionuclide scan areas of increased uptake. An MRI shows extensive replacement of the L2 vertebral body with tumor and a soft tissue mass at L1-2 impinging on the lowest portion of the spinal cord above the cauda equina. Diagnosis The rapid increase in PSA along with the imaging studies confirms reoc- strength, sensory loss in a saddle distribution, and greater loss of ankle than knee tendon reflexes. Subacute lesions can produce spastic bladder and impotence characteristic of conus medullaris syndrome. The options for management are wideranging and include glucocorticoids, androgen deprivation, radiation therapy, and surgical decompression. Discussion Numerous studies have shown that the most important determinant of outcome in malignant spinal cord compression is early diagnosis.16,17 MRI evaluation is the most sensitive diagnostic procedure when accompanied by heightened awareness of the potential threat. Prostate cancer, due to its predilection for axial skeletal metastases, is a frequent cause of cord compression, and patients should be instructed to bring bladder, bowel, and muscle strength changes to the physician’s attention as early as possible. While glucocorticoids and radiation therapy have been mainstays of treatment, a recent randomized trial of decompressive surgical therapy in addition to these modalities suggests a superior outcome in appropriately selected patients.18 However, for prostate cancer, immediate androgen deprivation in the hormone-sensitive patient may be equally important. The traditional approaches to androgen deprivation are surgical orchiectomy or medical castration using estrogens, ketoconazole, antiandrogens, or gonadotropin-releasing hormone (GnRH) analogs. The effectiveness of ketoconazole in prompt reduction of androgens is well documented, but fraught with significant side effects, including adrenal insufficiency.19 Surgical castration is both therapeutically effective and cost effective, but psychologically undesirable to many patients. Antiandrogens alone may be inadequate to completely suppress androgenic activity in the acute or chronic setting. Of particular concern is the use of luteinizing hormone-releasing hormone agonists that cause an initial surge in testosterone and may result in clinical flare of disease. The recent US Food and Drug Administration approval of a GnRH antagonist, abarelix, offers a new option for the management of prostate cancer patients at risk for spinal cord compression. In an open-label trial, prompt reduction in testosterone and PSA level was documented, making this form of monotherapy a preferred option among patients who refuse surgical castration. In this study, no patient with impending neurologic compromise developed spinal cord compression.20 [Leonard Michael Glode, MD] Case 4: Adjuvant Therapy A 53-year-old postal employee presented for a free screening exam. His digital rectal examination was equivocal with questionable asym- VOL. 6 SUPPL. 7 2004 REVIEWS IN UROLOGY S43 Case Reports continued metric firmness. His prostate-specific antigen (PSA) level returned from the screening sponsors at 5.6, and 4 of 12 biopsy cores had Gleason 7 (4 + 3) adenocarcinoma. He discussed therapeutic options and elected radical retroperitoneal prostatectomy. The final pathology report returned indicating positive capsule penetration, a positive surgical margin, and seminal vesicle invasion. Lymph nodes are negative. He has made an excellent recovery from surgery in the last 6 weeks with return of continence. He and his wife remember the discussion of having successfully removed all cancer the day after his surgery. Diagnosis It is now clear that accurate prognostic statements cannot be made until the final pathology is known. Patients appreciate optimism, but also clearly expect accurate information. “We got it all” or similar statements may reflect your personal confidence, but can compromise later counseling efforts. As with breast cancer, patients now access highly sophisticated tables, nomograms, and other sources and expect their final pathology results will be discussed. In this case, entry of the detailed pathology at www.nomograms.org reveals a 5-year progression-free survival rate of only 15%.21 Treatment Options The immediate short-term option for consideration in this case is radiotherapy. Early use of adjuvant radiation may improve the biochemical freedom from relapse.22 Longer-term challenges include the frequency of follow-up, the use of androgen deprivation, and most recently, the potential for adjuvant chemotherapy to improve cure rates. Discussion Neoadjuvant/adjuvant hormone deprivation in high-risk prostate cancer has been shown to improve diseasefree rates and overall survival in patients treated with radiotherapy. The optimal duration and timing of adjuvant hormonal treatment is the subject of ongoing research trials.23 There are no large-scale trials of adjuvant hormonal deprivation following surgery. One small trial, however, suggests not only a disease-free advantage, but an overall survival advantage for patients who received immediate androgen suppression versus waiting for tumor recurrence.24 These data are strongly supportive of immediate hormonal treatment for this patient. The optimal duration of such treatment, however, is unknown. Main Points • The relative risk for development of prostate cancer recurrence is dependent on various preoperative and postoperative clinical and pathologic factors. The most significant independent predictors are preoperative prostate-specific antigen (PSA), pathologic T stage, and final Gleason score (based on the prostatectomy specimen). • The National Cancer Institute's intergroup study 9921 (or SWOG 9921) is a clinical trial that practicing physicians and patients should explore vigorously. In this study, high-risk patients following radical prostatectomy are randomized to receive 2 years of androgen deprivation versus androgen deprivation and 6 months of the combination of mitoxantrone and prednisone. • The use of a gonadotropin-releasing hormone (GnRH) antagonist (abarelix) in this setting was critical in view of the severity of symptoms and need for rapid therapeutic effects. • Evolving data with new chemotherapeutic approaches suggest that nonhormonal treatment plays a significant role in the treatment of patients with hormone-resistant prostate cancer. • Prostate cancer, due to its predilection for axial skeletal metastases, is a frequent cause of spinal cord compression, and patients should be instructed to alert their physician about bladder, bowel, and muscle strength changes as early as possible. • Immediate androgen deprivation may benefit prostate cancer patients at risk for spinal cord compression. Traditional approaches to androgen deprivation are surgical orchiectomy or medical castration using estrogens, ketoconazole, antiandrogens, or GnRH analogs. • Recent US Food and Drug Administration approval of abarelix, a GnRH antagonist, offers a new option for the management of prostate cancer patients at risk for spinal cord compression. In an open-label trial of abarelix, prompt reduction in testosterone and PSA was documented, and no patient with impending neurologic compromise developed spinal cord compression. • Neo-adjuvant/adjuvant hormone deprivation in high-risk prostate cancer has been shown to improve disease-free rates and overall survival in patients treated with radiotherapy. The optimal duration and timing of adjuvant hormonal treatment is the subject of ongoing research trials. • Available evidence suggests that earlier application of chemotherapy (as opposed to waiting until hormone refractory disease emerges, or even the first appearance of PSA relapse) offers increasing hope for cure of high-risk patients. S44 VOL. 6 SUPPL. 7 2004 REVIEWS IN UROLOGY Case Reports Patients rarely die from local recurrences of cancer. Adjuvant chemotherapy was definitively proven to be of benefit in many stages of breast cancer more than 30 years ago. Incremental improvements in drug choices, patient characteristics, and sequencing of multimodal treatment have resulted from tens of thousands of women and their physicians participating in clinical trials. Prostate cancer therapy lags far behind these advances because so few men, as in the case of the patient discussed here, are placed in clinical trials. The Southwest Oncology Group (SWOG) trial 9921 is an ongoing randomized trial specifically designed to determine whether 6 cycles of chemotherapy (mitoxantrone + prednisone for half the participants) added to 2 years of combined androgen blockade (for all participants) can improve survival. This trial is widely available across the United States through the National Cancer Institute (NCI) (www.cancer.gov) and should be supported by all urologic surgeons. Similar trials will soon be available utilizing docetaxel-based chemotherapy. Every available evidence suggests that earlier application of chemotherapy (as opposed to waiting until hormone refractory disease emerges, or even the first appearance of PSA relapse) offers increasing hope for cure of high-risk patients. [Leonard Michael Glode, MD] References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. 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Treatment and prognosis of patients with paraplegia or quadriplegia because of metastatic spinal cord compression in prostate cancer. Prostate Cancer Prostatic Dis. 2003;6:169-173. Yalamanchili M, Lesser GJ. Malignant spinal cord compression. Curr Treat Options Oncol. 2003;4:509-516. Regine WF, Tibbs PA, Young A, et al. Metastatic spinal cord compression: a randomized trial of direct decompressive surgical resection plus radiotherapy vs. radiotherapy alone. Int J Radiat Oncol Biol Phys. 2003;57(suppl2):S125. Sarver RG, Dalkin BL, Ahmann FR. Ketoconazole-induced adrenal crisis in a patient with metastatic prostatic adenocarcinoma: case report and review of the literature. Urology. 1997;49:781-785. Koch M, Steidle C, Brosman S, et al. An openlabel study of abarelix in men with symptomatic prostate cancer at risk of treatment with LHRH agonists. Urology. 2003;62:877-882. Diblasio CJ, Kattan MW. Use of nomograms to predict the risk of disease recurrence after definitive local therapy for prostate cancer. Urology. 2003;62(suppl 1):9-18. Review. Valicenti RK, Gomella LG, Ismail M, et al. The efficacy of early adjuvant radiation therapy for pT3N0 prostate cancer: a matched-pair analysis. Int J Radiat Oncol Biol Phys. 1999;45:53-58. Pisansky TM. Use of neoadjuvant and adjuvant therapy to prevent or delay recurrence of prostate cancer in patients undergoing radiation treatment for prostate cancer. Urology. 2003;62(suppl 1):36-45. Review. Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with nodepositive prostate cancer. N Engl J Med. 1999;341:1781-1788. VOL. 6 SUPPL. 7 2004 REVIEWS IN UROLOGY S45