Fig. 14.1
(a) Ancient Scythian with metastatic prostate cancer to bone. (b) Marie Curie visiting New York City. (c) The Proton Accelerator at M.D. Anderson’s Cancer Center
Prostate cancer is widely believed to have occurred in ancient humans, though other animals such as rodents and canines also have been discovered to develop prostate cancer [6]. Giovanni Battista Morgagni described both the benign enlargement of the prostate as well as a case he assumes is cancer as well. Matthew Baillie (1761–1823) also had such a case in his classic work, The Morbid Anatomy of Some of the Most Important Parts of the Human Body [7]. He even states that “the most common disease of the prostate gland is scirrhus.” In Benjamin Brodie’s textbook of genitourinary diseases he states, “I have observed that malignant diseases of the prostate are of rare occurrence” [2]. It is in his textbook that he described the 60 year old male who would die of metastatic disease with spinal cord compression. He tried to get an autopsy on this gentleman but was unfortunately denied. Now we come to the work of Walter Hayle Walshe (1812–1892), an Irish physician who trained in Edinburgh. He had travelled to Paris and worked with Pierre Charles Alaxandre Louis and Francois L.I. Valleix and became interested in the microscopic investigation of diseased tissues. In 1836 he began to practice in London and was appointed as Professor of Anatomy at the University College of London. He published his most famous work The Nature and Treatment of Cancer in 1846 which contained all of the known data about cancer at that time, plus much of his own pathologic findings [8]. The book was organized in two parts—Part One was on the general principles of cancer and had eight chapters; Part Two was on cancers of particular parts and had twelve chapters. It is Chapter V of this section that was titled Cancer of the Urinary Organs that we will pay specific attention to his discussion on prostate cancer, where he essentially had collected the world’s data on this malignancy. He began by mentioning that M. Tanchou’s tabulated autopsy information on cancer deaths of 8289 fatal cases, only five were from the prostate [8]. He related both of Brodie’s cases and noted further cases from M. Mercier the size of an ostrich’s egg and two cases from M. Civiale. He noted, “that cancer affects the prostate as a distinct tumor, or infiltrates the organ more or less extensively. The size of the mass thus produced may, as the descriptions show, be very considerable. All three lobes of the gland appear prone to suffer from the disease; the middle is almost always mentioned as having been specially implicated” [8]. He then notes the progressive, lethal nature of the disease. “In all cases on record, except that of Mr. Stafford, cancer of the prostate has proved a disease of advanced life…The duration of life after the outbreak of symptoms in these cases has varied between a few months and several years” [8]. He went on to recount how the diagnosis is confirmed. “Examination with the catheter and the finger per rectum, coupled with consideration of symptoms, will commonly render the existence of prostatic tumor matter to certainty” [8]. Finally he espoused the known therapeutic options. “The treatment must be purely palliative; and the best palliation is afforded by the carefully managed use of the catheter; especially the elastic-gum kind. In cases of total retention, puncture of the bladder might become necessary; the operation above the pubes is probably the one to be preferred” [8].
In 1851, John Adams, a surgeon and lecturer on Anatomy at the London Hospital, published his The Anatomy and Diseases of the Prostate Gland [9]. He mentions George Langstaff’s case of sarcoma of the prostate. He discusses the physical examination as follows, “A schirrhous prostate conveys to the finger, passed per anum, a sense of gristly hardness, and is usually irregularly nodulated, one lobe being especially affected” [9]. He also described the sarcoma of the prostate in two cases of children, each about the age of three who rapidly died of their disease. In 1853, Adams also reported on a case of a man age 59 that died of prostate cancer with some histological slides from his prostate and lymph node metastases. In 1860, Henry Thompson wrote his Jacksonian Prize winning treatise, The Diseases of the Prostate, Their Pathology and Treatment [10]. To the world’s literature, Thompson would add 22 cases, 16 adults and 6 children, tabulating them nicely (Fig. 14.2a). He had very little more to offer, he also recommended the use of opioids when the pain became intolerable and discussed a bit more about the management of hematuria , which he believed was more common than the previous authors. Harrison tried surgery for prostate cancer in 1885 and stated, “Progressive cancer of the prostate resembling some features of hypertrophy is far more common than is generally believed to be the case” [11]. Billroth attempted surgical interventions in 1867, Fuller in 1898, Young in 1905. The progressively radical nature of the surgeries and the ultimate demise of the patients resulted in attempts to refine the indications and develop newer strategies for treatment. Harrison lamented, “…neither castration nor vasectomy is at all likely to be of any avail” [11]. But his comments were premature and not associated with the degree of comparison, controlling many factors that would be necessary for this understanding—but it was coming.
Fig. 14.2
Early treatment failures. (a) Thompson’s list of failed therapies. (b) Image from Deaver’s paper. (c) Deaver’s listing of failures. (d) Hugh Young’s list
In 1891 Friedrich Daniel Von Recklinghausen (1833–1910) was one of Virchow’s protégés described the osteoblastic variety of bone metastases that typify prostate cancers [12]. Franck Sasse described a patient presenting with bone pain from metastases in 1894 [13]. The other feature of metastatic prostate cancer was described by Octave Pasteau (1870–1957) when he noted the involvement of the iliac lymph nodes in 87% of cases whereas the inguinal nodes were only involved in 36% of these advanced cases [14]. George Blumer followed this case report and a review of the literature in 1902. He was able to extract from the literature 43 such cases, of which 16 of the total were recorded by Kaufmann. In 22 of these cases, the bones were examined and 70% showed metastatic disease and he states, “Considering the frequency of prostatic carcinoma it is easily realized that many instances of bone metastases must have been overlooked in the past. If bone metastases occur in such a large proportion of cases of carcinoma of the prostate, it is important to know whether the condition can be recognized clinically” [15]. He goes on to recount how this might be possible, “Of the general symptoms emaciation and weakness were most frequently mentioned. Pain of a general character in all the bones, or more local pain in the back and legs was also common. Anemia was noted in some cases, though there are but few records of blood examinations and most of these show merely a secondary anemia” [15]. He does go on to mention the condition originally described by Sir Benjamin Brodie that began this section of our history, namely metastatic paraplegia. “Those with more or less marked paraplegia numbered 8 out of the 23 cases. In 4 of these the paraplegia was complete and accompanied by the usual sensory changes, the lack of sphincter control, and the exaggerated reflexes. In the other 4 cases the paralysis was incomplete” [2].
John Hunter (1728–1793) described the seasonal variations in the size of testicles and compared them to the prostates of various animals. In addition, he surgically removed the testicles and observed the effect upon the prostate [16]. In 1893, W. J. White of Philadelphia reported on the castration of dogs resulting in the atrophy of the glandular mass of the prostate. He advocated castration for the treatment of symptomatic men [17]. Clyde Deming and the group at Yale did studies on primates, also noting atrophy of the prostate in castrated males [18]. Robert Moore and Allister McLellan discovered that female hormones also had activity upon the prostate [19]. In 1936, in was reported that various phosphates were elevated in men with skeletal metastases from prostate cancer. Charles Brenton Huggins (1901–1997) was a Canadian-born physician, attended Harvard’s Medical School before going to the University of Michigan for his internship and specialty training in urology. He moved to the University of Chicago where he became interested in the hormonally-induced regression of prostate cancer [20]. In 1940 he published Quantitative studies of prostatic secretion. 11. The effect of castration and of estrogen injection on the hyperplastic prostate glands of dogs [21]. He followed this with The effect of castration on benign hypertrophy in man [22]. Finally in 1941 his paper, Studies on prostate cancer: 1. The effects of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate was published [23]. He was given the Nobel Prize in Physiology and Medicine in 1966. “Prostatic cancer is influenced by androgenic activity in the body. At least with respect to serum phosphatases, disseminated carcinoma of the prostate is inhibited by eliminating androgens, through castration or neutralization of their activity by estrogen injection” [20]. In that same fateful year, Huggins also presented the case for oral estrogen administration by stilbesterol. In the 1960s the Veterans Administration Cooperative Urologic Research Group (VACURG) noted in one of the largest randomized studies performed, noted the beneficial effects of androgen ablation in men with advanced prostate cancer as well as confirming the significant cardiovascular sequeallae of estrogens [24]. Huggins continued to contribute by noting that the adrenals also contributed androgens and that bilateral adrenalectomy did offer some response. Andrew Schally discovered the structure of the hypothalamic hormone LHRH in 1971 and developed agents to manipulate this system including LHRH agonists and antagonists [25]. He would go on to win the Nobel Prize in 1977 [26]. Anti-androgens were discovered to be synergistic to the effects of hormone suppression with the first agent being aminoglutethimide and the antifungal agent ketoconazole. Steroidal and non-steroidal antiandrogens showed relative poor response to advanced prostate cancer alone, with much better results used in combination with LHRH agents. None of the agents or combinations of agents however cured the patient with metastatic prostate cancer, but improved survival rates only [27].
Early Therapeutic Failures
Surgery for the treatment of prostate cancer was not as dramatic as for other genitourinary cancers, partially because of the deep pelvic location of the prostate, surrounded on all sides by anatomical potential disaster—the bladder above, the rectum posteriorly, and large veins and plexuses of veins all around. In 1852 Jean Nicolas Demarquay used the perineal approach common in stone disease to approach the prostate. Küchler in 1866 is given credit for developing the strategies necessary for performing a complete, if not radical perineal prostatectomy in Berlin on cadavers. But it fell to the great Theodor Billroth (1824–1923) who attempted to remove a large tumor “about the size of a duck’s egg” from a 30 year old man in 1867 that died of recurrence 14 months after the surgery. He tried again that same year but this patient survived only a few days [28]. Bernhard Rudolph Conrad von Langeneck (1810–1887) also tried to excise cancerous prostate via the perineum in 1876, this was observed by his pupil Heinrich Wilhelm Franz Leisrink who went on to perform a radical perineal prostatectomy in 1883 but the patient died on the 14th postoperative day [29]. The great Austrian surgeon Vincenz Czerny (1842–1916) also tried total prostatectomy twice—both died 12 days to 9 months following the surgery [29]. In 1891, Georg Ferdinand von Kóster (1839–1930) tried a combined total cystectomy along with a perineal prostatectomy with implantation of the ureters into the sigmoid colon, but the patient died 5 days afterwards [29]. In 1904, a new radical perineal approach had been devised by Hugh Hampton Young (1870–1945), and he had his Chief, William Stewart Halsted (1852–1922) assist on his first case and a year later reported upon his first six cases [30]. He stresses the necessity of discovering the cancers early. “An inverted V cutaneous incision was made in the perineum…By blunt dissection the end of the bulb and central tendon were exposed, and the latter divided, exposing in turn the rectourethralis muscle, the division of which gave free access to the membranous urethra behind the triangular ligament. Urethrotomy upon a grooved staff, was followed by introduction of the prostatic tractor, which was opened out after it reached the bladder…the lateral attachments, which are slight were easily separated by the finger…The posterior surface of the seminal vesicles were then freed by blunt dissection, the now mobile prostate being well out of the wound. In this exposure of the posterior surface of the vesicles I was careful not to break through the fascia of Denonvillier’s. The next step was to expose the anterior surface of the bladder, which was easily done by depressing the tractor and making strong traction…it was easily incised at a point in the middle line about one cm. behind the prostatovesicular juncture. By means of scissors the division was continued on each side until the trigone was exposed…the line of incision was carried across the trigone with a scalpel so as to pass about one cm in front of the ureteral orifices…thus exposing the anterior surface of the seminal vesicles and the adjacent vasa deferentia, all of which were carefully freed by blunt dissection with the finger as high up as possible, so as to remove with the vesicles much circumjacent fat and areolar tissues on account of the lymphatics which they contained” [30]. The first patient did well except for incontinence only to develop stones upon the silk sutures used to perform the anastomosis and undergoing a litholapaxy developed extravasation of urine dying about 4 weeks later. An autopsy revealed that a small focus or cancer was found along the left vas deferens, but no other foci could be identified. In later long-term follow-up studies, Young noted that only about 50% of surgical patients were alive at 5 years in 1937 (Fig. 14.2d). His protégé J. A. C. Colston by 1940 had obtained no better results, except in the degree of incontinence but the same 50% 5-year cancer survival was not very good [31]. Better diagnostic strategies and improved imaging studies were required. Terence John Millin (1900–1979) did develop a retropubic surgical approach in 1947 that seemed to make the surgical approach easier for urologists, as well as sample the pelvic lymphatics in an expanded methodology and this was followed in Philadelphia by Deaver [32]. (Fig. 14.2b and c]. Patrick C. Walsh (1938-) developed the anatomical radical retropubic prostatectomy in 1983 and brought forth the new wave of radical surgeries [33]. For surgery to progress, a tumor marker that isolated the cancers to earlier grades and stages was necessary and the discovery of prostatic specific antigen represented this needed impetus. Next, the complications and side-effects of surgery could be addressed. Finally, the type of surgery could reduce the trauma to the patient and laparoscopic radical prostatectomy begat robotic-assisted radical prostatectomy and the future interventions will come of their own accord [34]. The failure of early historical surgery and the rise of improved technology in radiation therapy represented the next major accomplishments in the management of prostate cancer.
Radiation and History
“What can be easier than to turn the rays on the lungs of persons afflicted with consumption.” Thomas Edison, February 1896.
Perhaps given the poor results of surgical intervention in the pre-PSA era, radiation treatments were hoped to add to the patient’s survival. Radiation was just discovered by Antoine Henri Becquerel (1852–1908) in 1896. Wilhelm Conrad Röntgen (1845–1923) won the very first Nobel Prize in 1901 for his discovery of X-rays in 1895 and Marie Curie-Sklodowska (1867–1934) with her husband Pierre Curie (1859–1906) discovered radium in 1898 (Fig. 14.1b). The biologic effects of X-rays were described in hand injuries by O. Leppin in 1896. Leopold Freund (1868–1943) used Röntgen rays for treatment of a naevus pilosus with tragic results in 1896. The first skin cancer was treated in 1899 by Thor Stenbeck (1864–1914) and prostate cancer followed in 1904 by Armand Imbert (1850–1922) [35]. Nikola Tesla in 1896 speculated for the New York Times, “it might be possible to load X-Rays with cancer-fighting drugs or chemicals and project them into the body” [36]. The beams of the X-rays were not well configured but early reports by E. Loumeau reported favorable responses. The use of radium was introduced by M. Minet and Ernst Desnos by radium catheters in 1908, the Gussenbauer Clinic in Vienna followed in 1902 and Hugh H. Young at Johns Hopkins also adapted applications for use. But no one literally knew how the new X-rays actually worked, though by 1906 Tribondeau and Bergonié stated, “The effects of irradiation on the cells are more intense the greater their reproductive activity, the longer their mitotic phases, and the less their morphology and functions are established” [37].
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