Metastatic Prostate Cancer: A Case Study

Introduction

This paper will review a case study in what is called metastatic prostate cancer in a patient experiencing castration-resistant prostate cancer (CRPC). This paper is divided into six sections.  The first section is the introduction to the subject of the paper.  Section two will discuss the anatomy and background related to the topic area.  Section three will provide a case study of the topic area.  This section will include the patient's medical history, imaging data, and patient follow-up.  Section four will discuss imaging features for typical cases and contrast them with those in the case study.  Section five is the discussion of the disease pathology. Section six is the summary and conclusion for the paper.

Prostate cancer's importance as a global affliction with potentially serious health implications is considerable.  With the exception of non-melanoma skin cancer, prostate cancer is the most common cancer affecting men in Western countries in general.1, 2 It is also the primary cause of cancer mortality in men.2 According to research, more than 240,000 men are expected to be positively diagnosed with prostate cancer in the US in 2011, of which over 33,000 would die of the disease.3 This is a significant increase from 2009 when over 192,000 cases were expected with over 27,000 deaths.2(186)

The rationale for the selected case study is a closer examination of the issues inherent in the minority of cases in which the cancer has spread to other organs.  More particularly, what differentiates metastatic prostate cancer from its localized version?  Also, what can be done to significantly improve the survival outcomes of metastatic prostate cancer patients.  The focus of this paper will be on a subset of metastatic prostate cancer patients who are resistant to hormonal therapy. CRPC occurs when the disease progresses despite hormone therapy treatment. The typical period from the initiation of treatment to the progression of the pathology can vary from years to even longer depending on the patient.

Pertinent Anatomy

The prostate is a gland in the reproductive systems of men.  The gland is located in the pelvis.  It's posteriorly surrounded by the rectum and superiorly surrounded by the bladder. The gland's normal function is not yet well understood.16 However, function is commonly associated with the production of seminal fluid which facilitates sperm motility. The gland itself is comprised of branching glands.  These glands have ducts lined with epithelial cells and basal cells which secrete fluid.  A paracrine function to the gland is deduced from sprinkled neuroendocrine cells. The epithelial cells are dependent on androgen for development and generate prostatic acid phosphatase and PSA. The basal cells are thought to contain the stem cell population for the epithelial cell layer and do not contain androgen for development.16 The gland's environs include a stroma.  The stroma includes such features as lymphatics, nerves, smooth muscle, and fibroblasts.  Although the interactions between the Stroma and epithelial cell layer are not well understood, it's thought to create a number of growth factors, including muscle development and testosterone levels, crucial to the development of both the normal prostate and prostate cancer.

In most cases, prostate cancers grow quite slowly and are localized.   However, there are cases of aggressive cancers which can metastasize to other parts of the body.  Figure 1 shows a side by side comparison of a healthy prostate with a prostate that is enlarged.  It also shows the location of the prostate gland inside the reproductive systems of males.  It is possible that enlarged prostates can be benign. This is the case with normal and hyperplasia. A digital rectal examination, used prior to the introduction of the PSA test, mistook those for prostate cancer.2(187)

(Figure 1 omitted for preview. Available via download)

Patient Medical History

Case study details are taken from Periyakoil's case study details.4 A 63-year-old Filipino male who suffered from CRPC or hormone-refractory prostate cancer.  There is not much family medical history available for the patient.  However, the patient was born and raised in the Philippines.  He only lived in the US for a few years prior to diagnosis and that was thanks to sponsorship from his sister. The patient has been married for 35 years and has three adult children4.

The patient was diagnosed with benign prostatic hypertrophy (BPH) several years ago for which alpha-blockers were prescribed as treatment.  However, the patient's condition began to decline. A digital rectal examination found a solid nodule located on the right lobe of the prostate. The PSA returned a value of 2.4 which was up from the previous year's 2.2 score.  A biopsy was conducted which uncovered an adenocarcinoma of particularly high grade in 5/5 R lobe biopsy samples.  These specimens returned a Gleason's score of  4+5, and 2/5 of L lobe biopsies. The prostate cancer was diagnosed at stage T2b4. The patient had the following medical conditions.

(Table omitted for preview. Available via download)

At the time the diagnosis was made, the patient was examined by Oncology and Radiation Oncology.  The recommendation was for the patient to undergo external beam Intensity Modulated Radiation Therapy.  This was to be followed by hormone therapy and a possible trial involving Taxotere4.

(Figure 2 omitted for preview. Available via download)

After six months the patient, as recommended, was placed on radiation therapy focused on his prostate and pelvic lymph nodes. He was placed on hormonal therapy and given a Taxotere trial.  The patient complained of persistent low back pain.  So an MRI was performed which revealed bony metastasis of the L2 and L3 spine.  He received radiation therapy to the spine as well4.

For the patient in the study, some pertinent facts stand out.  First, the patient was a recent immigrant to the US from the Philippines. Therefore he may not have had access to health care which could have diagnosed and treated his pathology before it advanced to a particularly aggressive stage. This is likely speculative, but it may be the patient's cancer had become so advanced and spread so widely that it was simply beyond existing therapies to effectively contain or remove it.  This is a cautionary tale for other men with prostate cancer to seek out treatment options as early as possible.  As noted above, the median survival rate is much higher than in this particular case with early detection.

(Figure 3 omitted for preview. Available via download)

After nine months, the patient disclosed he was experiencing worsening pain in his back, flank, rib, and leg.  Taxotere was initiated for the second time.  In a follow-up examination the same month, a bone scan revealed uptake had grown in the skull, ribs, and thoracic and lumbar spine.  Also notable was the not as dramatic uptake in the proximal L femur.  PSA score was 48.4.  Uro-oncology examined the patient who treated him with mitoxantrone and prednisone given each in two courses.  The patient's pain was reduced for a time with hydromorphone patient-controlled anesthesia.  He is now on 80mg of methadone with a dose given once every eight hours4.

At the most recent time, which is eleven months after the first diagnosis, the patient reports the current pain regimen is providing him with some relief. However, he reports both persistent poor appetite and fatigue. On the positive side, he can perform his activities of daily living without assistance and can even work occasionally. The patient's weight was recorded at two pounds below his last visit which was two months ago. The patient is also mentally alert and not disoriented.  His most recent laboratory report shows a PSA of 70.74.

The patient's Karnofsky Performance Scale (KPS) score is estimated at 70%.  This is for a patient that is able to care for oneself but is unable to perform normal activities or active work.5(196) The predicted prognosis is three months for a typical patient with these conditions.  Metastatic prostate cancer is incurable.  Thus treatments are mainly palliative and provide modest survival benefit at the stage this patient has reached.4

Although imaging for the patient is not available at the time this paper was prepared below are presented images from a patient with similar conditions. Below in figure 2 are three images of a bone scan.  The scans are from a patient with metastatic prostate cancer and the dark areas on the scan reveal the spread of cancer to the bones.

(Figure 4 omitted for preview. Available via download)

The scanning procedure involves injecting radionuclides into the patient's arm about three hours before the scan.  The radionuclides disperse throughout the body and they can reveal areas in the body, called hotspots. The hotspots are distinguished by abnormal blood flow which can be an indication of cancer.  However, it can also be an indication other diseases are present, such as osteoarthritis.  As a result, additional testing is needed to clarify the result.

(Figure 5 & 6 omitted for preview. Available via download)

Imaging Features

Three different cross-sectional imaging modalities have been tested in prostate cancer patients. These are computed tomography(CT), ultrasonography, and magnetic resonance imaging(MRI).13  Of the three, magnetic resonance imaging has emerged as the most consistently used modality in the detection, planning of treatment, and patient follow-up examinations related to prostate cancer.13 Interest in the multiparametric MRI has increased considerably. This imaging modality uses anatomic T2-weighted (T2W) imaging with magnetic resonance spectroscopic imaging (MRSI), dynamic contrast-enhanced MRI (DCE-MRI), and diffusion-weighted imaging (DWI) in combination.

According to recent research, using either the T2W MRI and DWI or the MRSI with DCE-MRI has been shown to effectively direct biopsy to the most aggressive foci in prostate cancer patients who previously had shown negative biopsies. Thus, this imaging modality improves procedural precision).13 In addition, including MRSI, DWI, and either or DCE-MRI to T2W MRI, facilitates improved preoperative characterization of the pathology.  This would be in terms of the location, size, and relationship of the pathology to prostatic and extra-prostatic features.  It's also believed useful in early recognition of local recurring disease.13 So the various MR imaging techniques may provide notable improvement in surgery, oncology, and functional management.

Normal appearance. The prostate gland can be divided into four zones or regions.  These are the periphery, transitional, central, and the anterior non-glandular fibro-muscular stroma. About 70-80 percent of glandular tissue is located in the peripheral zone. This is the zone where about 70 percent of the prostate cancers develop.14 The transition zone is where 30 percent of the cancers develop. The central and transition zones can't be differentiated on T2-weighted (T2W) images. They are collectively defined as the central zone.  This zone is marked off from the periphery by means of a pseudo-capsule of thin texture.  T2W images show the periphery as having high signal intensity.  This intensity is notably equal or higher than that of adjacent fat. The intensity is believed to be caused by ductal and acinar components which are filled with fluid. The increase in the signal intensity is also related to age.14 The central gland has low T2 signal intensity because it has smooth muscles and fewer glandular structures.  This gland may appear heterogeneous in appearance because nodules and cysts are present. The true capsule is visible in the low-intensity rim. It's an important landmark in prostate cancer imaging because the extra-capsular extension (ECE) can outshine the tumor to T3.14 At 5 and 7 o'clock locations neurovascular bundles are usually visible. The neurovascular bundles have branches that penetrate to the top and base of the gland.  These branches serve as crucial routes by which the tumor spreads outside the capsule. Seminal vesicles are visible on low signal T1-weighted images.  They appear as formations filled with fluid and having septae of thin texture .14 The vas deferens displays low signal intensity on T1 and T2 images and is viewable as a tubular formation medial to the seminal vesicles.

According to the European Consensus Meeting, the prostate gland is divided between 16 and 27 areas of interest.  The Meeting provided guidelines that assessed a score to each area on a scale of one to five. A score of one indicates that there was a very small likelihood that a clinically significant disease was present.  Conversely, a score of five indicates that clinically significant pathology was very likely present. Clinical significance is defined as the patient having a lesion with ≥0.5 cm3 volume along with a Gleason score of ≥4 + 3.14

Pathology appearance, features and differential diagnoses. Peripheral area cancer foci appear on T2W imaging as circular or poorly defined regions of low signal intensity lesions. It should be noted that these imaging features are similar to other kinds of formations including prostatitis, hemorrhage, benign hyperplasia, atrophy, and organ changes related to treatment.14   It's usually recommended that the radiologist compare the imaging findings with other factors.  These factors include the timing and inference of prostate biopsy, the serum prostate-specific antigen (PSA) level, the Gleason score, and the clinical findings on the patient's digital rectal examination.14  T1W images can provide differentiation between the post-biopsy hemorrhage and the prostate cancer foci.  Also, the post-biopsy hemorrhage is viewable as a hyper-intense signal on T1W imaging.14  Therefore, following the recommendations above can provide a more accurate diagnosis and avoid the possibility of false-negative due to a hemorrhage overlay. The prostate MRI is commonly conducted about six to eight weeks after an endorectal biopsy.14

Tumors in the transitional zone are viewable on T2W images as lesions with low-signal intensity.  They have a lenticular shape with a poorly defined form and a capsule is noticeably absent.  Tumor localization in the central gland is complicated in the context of stromal hyperplasia.  This is due to the zone's heterogeneity of background. A diagnosis of benign prostatic hyperplasia (BPH) is favored by the presence of "well-defined margins, visible capsule, and round shape".14 Transitional zone tumors can spread to the anterior fibromuscular stroma.  However, BPH tumors are known to displace rather than spread to the fibro-muscular stroma. Validity and reliability. A study comparing MRSI-DCE-MRI with PET-CT was conducted in the identification of small lesions in patients having a low biochemical failure.  The study concluded that the multiparametric MRI was a valid tool to detect local recurrence. It was also found to be more accurate than the PET-CT.15 Conversely, there does not appear to be much literature discussing the reliability of the MRI.

Pathology Discussion

Causes. The case of prostate cancer is still undetermined.  In a general sense, there is some association between genetics and lifestyle factors.6(1439)  However, the exact nature of what factors are involved are still not precisely known.  Although some recent research into the differential impact of prostate cancer in black American men identified chromosome 8q24 as of further interest. 6(1439)

Some researchers have attempted to hypothesize more specific environmental factors as well.  But these factors are usually viewed as controversial in the literature.  Examples of such proposed causes include increased calcium intake10, smoking1, obesity10, being a member of certain racial groups2, lower socio-economic status6, and even seasonal conditions11.  It can only be said at this time, that prostate cancer affects mainly older men. Indeed, the risk factor for developing prostate cancer increases significantly for men over 50.  The incidence of prostate cancer in men under 50 is only 1 percent.2(191)

Black American men are said to have the highest rate of cancer incidence in the world.2  While men of lower socioeconomic status in all racial groups appear to have more serious prostate cancer diagnoses compared with men of higher socioeconomic status.  It is likely that lack of access to health care is a factor in their more serious pathologies for patients of lower socioeconomic status.  This factor naturally overlaps with race in the United States.

Zu and Giovannucci in their meta-study of longitudinal studies of men afflicted with prostate cancer present some compelling, if often non-statistically significant, evidence.2(1799)  The authors argue that a long term and heavy cigarette smoking habit is implicated in diagnoses for some of the more serious prostate cancer cases.  This correlation was discovered in almost all of the longitudinal studies they reviewed.  The authors found that smokers have a higher rate of contracting prostate cancer than non-smokers. They also note that ex-smokers have a higher probability of developing prostate cancer than non-smokers, although their risk was lower than that for smokers.   In their view, researchers should look more closely at the smoking habits of prostate cancer patients especially in the last ten years before diagnosis. 

Colloca and Venturino conducted a study of the family history of prostate cancer. The authors argue that the heredity and lifestyle factors, implicated as causal in prostate cancer, need to be more sharply examined.12(14-15)  In their view, the place where heredity and lifestyle factors intersect is in the family.  The authors present evidence that the likelihood of developing prostate cancer increases for all males in the family if at least one brother has been diagnosed with the disease.  This is thought to be even more predictive than if a father was diagnosed with the disease. The authors argue that researchers have to look more closely at families where prostate cancer cases are known to cluster.  They should use such cases to further investigate environmental and genetic causality of the pathology.

Symptoms. Prostate cancer does not usually exhibit symptoms, particularly in the early phases of the diseases.  This means that sufferers are commonly unaware that the cancer is growing during its long period of latency.  When the disease has reached an advanced stage, its symptoms are actually quite similar to other common urinary tract diseases and to conditions normal to aging.2 Thus early detection is rendered quite difficult without regular examination.

A major change in prostate cancer treatment has been the development of the Prostate-Specific Antigen (PSA) test.  This test has been quite a boon for prostate cancer treatment because it has more precisely quantified the incidence of infection in the population.2(187)  At the same time, the PSA test has raised questions about what treatment options are appropriate.7(853), 3(582)  Some research has noted that, early on in the use of the PSA test, treatment for prostate cancer was begun almost immediately.7(853),3(582)  It was not always recognized that the pathology of most prostate cancers differs from other types of cancer that can lead to much more metastatic and life-threatening outcomes.  However, the pathology in most prostate cancer cases is one of a localized phenomenon.

Treatment Options. Seventy percent of all prostate cancers involve localized pathology.6(1433), 7(853) That is, to say, the cancer remains restricted to the prostate, grows very slowly and the individuals suffering from the disease are far more likely to die from other causes. 7(853), 8(711)

It has been the case that, in localized prostate cancer cases, treatment regimens in recent years have shifted away from immediate treatment as the best option and have begun to look at various immunotherapies.  This is because the means to treat prostate cancer for more than 90 percent of the men are radical prostatectomy(RP), external beam radiation,  and brachytherapy (BP).7(853)  These treatment methods cause such problems as impotence, urinary or bowel-related dysfunction, and other long-term complications.3(582), 7(853) There is also the considerable expense involved in treatment.  Some estimates place the cost for treatment at $5 million to prevent a single morality.7(853) Therefore physicians have adjusted away from a one-size fits all treatment regimen to one that relies more on individualized care on a case by case basis. 7(853), 3(582)

Two treatment options for patients with localized prostate cancer are known as active surveillance (AS) and watchful waiting (WW).  These treatment interventions involve less aggressive strategies to treatment for localized pathologies.  AS is the appropriate therapy for younger men in whom the disease is deemed to be indolent.  This means that while immediate treatment is not required, active monitoring of the condition is. Methods used to evaluate the state of the disease include PSA testing, DRE, prostate imaging, and biopsy.  The more radical surgical or radiation treatments are only resorted to when it becomes clear that the disease is worsening.  This is still done with the patient's discretion. 3(582) Thus AS is the more curative intervention of the two strategies.

WW involves a more passive intervention.  It takes a more "wait and see" attitude toward symptom manifestation.  WW is deemed most appropriate for older men with localized prostate cancer. It is believed that these kinds patients won't benefit from aggressive radiotherapies. So in order prolong the potentially harmful side-effects of treatment a more patient approach is taken to treatment. 3(582)

The prognosis in most cases, where the cancer hasn't spread, is that the patients will likely expire from causes other than prostate cancer. 7(853), 3(582) As such the most aggressive interventions now involve cancers that are clearly progressive in nature and definitely metastatic. For patients with metastatic prostate cancer the median survival is reportedly as much five to six years. 9 There are some reports that the survival rate is much longer than that, but this is difficult to verify at the present time.9

Conclusion

Most prostate cancers are of a localized type, grow very slowly and do not pose a significant cause of mortality to the patient.  Therefore, in such cases, aggressive interventions are evaluated on an individualized basis.  However, for the minority of patients with metastatic cancer, aggressive therapies are indeed the recommended option.   For such patients, the prognosis can range from a few years to even longer.  Even within such patients is another subset who have cancers that are resistant to hormonal therapy.  Such patients may experience cancer that is too widespread to effectively manage.  In those cases, the intervention is mainly palliative or curative in focus.  As cancer is diagnosed in stages however, it is crucial that appropriate treatment is applied to the patient as early on as possible.

As the cause of prostate cancer is still not precisely understood, the best option is regular screening for prostate cancer for men over the age of 50.  It is likely that even in the case of metastatic prostate cancer, the earlier the diagnosis in the development of the pathology, the better the chances of long-term survival with the disease.  Also, the less likely the disease will advance to its metastatic or therapy-resistant versions.

References

1. Zu, K, Giovannucci, E.  Smoking and Aggressive Prostate Cancer: A Review of the Epidemiologic Evidence.  Cancer Causes Control, 2009; 20(10): 1799-1810.

2. Zhou, X, Bigler, SA, Pound, CR. Age Disparities in Diagnosis of Prostate Cancer Between African Americans and Caucasians. Ageing Int. 2012; 37:186–194. doi:10.1007/s12126-010-9104-x.

3. Dahabreh, IJ, Chung, M, Balk, EM, et al. Active Surveillance in Men With Localized Prostate Cancer: A Systematic Review. Ann Intern Med. 2012;156:582-590.

4. Periyakoil, VJ. Case Study: 63 Year Old Male With Advanced Prostate Cancer.  Stanford.edu, n.d.  http://endoflife.stanford.edu/M18_progn/case1_1.html.  Accessed Sept. 25, 2013.

5. Karnofsky, DA, Burchenal, JH. The Clinical Evaluation of Chemotherapeutic Agents in Cancer. Pg. 196. In MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. New York, NY: Columbia University Press, 1949.

6. Cheng, I, Witte, JS, McClure, LA, Shema, SJ, Cockburn, MG, John, EM, Clarke, CA. Socioeconomic Status and Prostate Cancer Incidence and Mortality Rates among the Diverse Population of California. Cancer Causes Control, 2009; 20(8): 1431-1440.

7. Hayes, JH, Ollendorf, DA, Pearson, SD, et al. Observation Versus Initial Treatment for Men With Localized, Low-Risk Prostate Cancer: A Cost-Effectiveness Analysis. Ann Intern Med. 2013;158:853-860.

8. Jayadevappa, R, Schwartz, JS, Chhatre, S, Wein, AJ, Malkowicz, SB. Qual Life Res. 2010; 19:711–720. doi: 10.1007/s11136-010-9622-8.

9. Long-term Survival of Patients with Metastatic Prostate Cancer. Prostatecancerinfolink.net, July 8, 2010. http://prostatecancerinfolink.net/2010/07/08/the-long-term-survival-of-patients-with-metastatic-prostate-cancer/.  Accessed Sept. 26, 2013.

10. Halthur, C, Johansson, ALV, Almquist, M, et al. Serum Calcium and the Risk of Prostate Cancer.  Cancer Causes Control, 2009; 20(7): 1205-1214.

11. Möller, H, Johansson, JE, Stampfer, M. Season of Diagnosis and Prognosis in Breast and Prostate Cancer.  Cancer Causes Control. 2009; 20(5): 663-670.

12. Colloca, G, Venturino, A. The Evolving Role of Familial History for Prostate Cancer. Acta Oncol, 2011; 50: 14–24.

13. Sciarra, A., Barentsz, J., Bjartell, A., et al. Advances in Magnetic Resonance Imaging: How They Are Changing the Management of Prostate Cancer. European Urology, 2011; 59(6): 962-977.

14. Hedgire, S. S., Oei, T. N., Mcdermott, S. et al.  Multiparametric magnetic resonance imaging of prostate cancer. GU Imaging, 2012; 22 (3): 160-169.

15. Alfarone, A., Panebianco, V., Schillaci, O., et al. Comparative analysis of multiparametric magnetic resonance and PET-CT in the management of local recurrence after radical prostatectomy for prostate cancer. Critical Reviews in Oncology/Hematology, 2012; 84, 109–121.

16. Oh, W. K., Hurwitz, M.,  D'Amico, A.V., et al. Biology of prostate cancer. Nih.gov. 2003. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK13217/.  Nov. 2013.