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Surgery - Procedures, Complications, and Results
Ovarian Cancer: The “Gynaecological Challenge” from Diagnostic Work-Up to Cytoreduction and Chemotherapy. Volume 1
Christos Iavazzo, Alexandros Fotiou, MD and John Spiliotis, PhD (Editors)
2023. ISBN: 979-8-88697-633-5 (Hardcover)
2023. ISBN: 979-8-89113-034-0 (eBook)
Nosocomial Infection in Abdominal Surgery
Andrés García Marín, MD, PhD and Jaime Ruiz-Tovar, MD, PhD (Editors)
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Names: Iavazzo, Christos, editor. | Fotiou, Alexandros, editor. | Spiliotis, John D., editor.
Title: Ovarian cancer : the "gynaecological challenge" from diagnostic work-up to cytoreduction and chemotherapy / Christos Iavazzo (editor), Metaxa Memorial Cancer Hospital, Piraeus, Greece, Alexandros Fotiou, MD (editor), Metaxa Memorial Cancer Hospital, Piraeus, Greece, John Spiliotis, PhD (editor), Department of Surgical Oncology and HIPEC, Athens Medical Centre, Athens, Greece; Department of Surgical Oncology and HIPEC, European Interbalkan Medical Centre, Thessaloniki, Greece.
Description: New York : Nova Science Publishers, [2023]- | Series: Surgery - procedures, complications, and results | Includes bibliographical references and index. |
LC record available at https://lccn.loc.gov/2023030101
LC ebook record available at https://lccn.loc.gov/2023030102
Published by Nova Science Publishers, Inc. † New York
Preface
Chapter 1 Ovarian Cancer Pathology and Surgery, Historical Pearls from the Pioneering Greeks and the General Term Gynecologic Cancer to Modern Histopathology and Ovarian Malignancy ................. 1 G. Tsoucalas, Christos Iavazzo and M. Karamanou
Chapter 2 Ovarian Cancer Screening
Aleksandra Gentry-Maharaj and Aarti Sharma
Chapter 3 The Role of Ultrasounds in the Diagnosis and Management of Adnexal Tumors
Natalie Nunes and Davor Jurkovic
Chapter 4 Preoperative Biomarkers to Predict Resectability of Patients with Ovarian
Valerio Mais, Michele Peiretti, Daniela Fanni, Maria Luisa Fais, Giulia Carboni, Giuseppe Deo, Giuseppina Fais and Stefano Angioni
Chapter 5 Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) Findings in Ovarian Cancer...........................................
Skouras Ioannis, Kokkali Kalliopi and Fotiou Alexandros
Chapter 6 The Role of 18FDG PET/CT Scans in Ovarian Cancer Patients
Lydia Iordanidou
Chapter 7 The Pathogenesis of Ovarian Cancer.....................................................
Victoria Psomiadou
Chapter 8 Inherited Ovarian Cancer-Linked Syndromes and Management
Malcolm Scott, Adam Rosenthal and Terri McVeigh
Chapter 9 Pathology of Epithelial Ovarian Tumors...............................................
Helen J. Trihia
Chapter 10 Pathology of Non-epithelial Ovarian Tumors
Christos Iavazzo, Alexandros Fotiou, John Spiliotis and Agathi Kondi-Pafiti
Chapter 11 The Role of Immunohistochemistry in Ovarian Tumors.....................
Christos Valavanis, Efthymia Souka and Gabriela-Monica Stanc
Chapter 12 Molecular Pathology of Epithelial Ovarian Tumors ............................
Christos Valavanis, Efthymia Souka and Gabriela-Monica Stanc
Chapter 13 An Approach to Borderline Ovarian Tumors.......................................
Maria Luisa Fais, Giorgio Candotti, Giulia Carboni, Giuseppe Deo, Giuseppina Fais, Valerio Mais, Stefano Angioni and Michele Peiretti
Chapter 14 Prophylactic Salpingo-Oophorectomy in High-Risk Patients
Paul I. Stanciu and Sabina Mistry
Chapter 15 The Management of Early-Stage Epithelial Ovarian Cancer..............
Virginia García Pineda, Violeta Romero and Ignacio Zapardiel
Chapter 16 Fertility Sparing in Ovarian Cancer Patients .......................................
Myriam Gracia, Ana Peralbo and Ignacio Zapardiel
Chapter 17 The Local-Regional Control of Ovarian
Paul H. Sugarbaker
Chapter 18 Surgical Management of Advanced Epithelial Ovarian Cancer .........
Federico Coccolini, Riccardo Guelfi, Enrico Cicuttin, Camilla Cremonini, Dario Tartaglia, Marta Carretto, Tommaso Simoncini and Massimo Chiarugi
John Spiliotis, Alexandros Fotiou and Christos Iavazzo
Miriam Turiel Miranda, Ignacio Cristobal, Elena Martin-Boado and Ignacio Zapardiel
Preface
We are proud to present our book entitled: "Ovarian Cancer: The "Gynaecological Challenge" from diagnostic work-up to cytoreduction and chemotherapy".
Ovarian cancer is one of the deadliest gynaecological cancers. In most cases, it is detected as an advanced tumor, since early diagnosis is challenging for most forms of the disease. Surgery and platinum-based compounds have been the mainstay of therapy for many years. The prognosis for ovarian cancer depends on the type of surgery and on the response to chemotherapy. Other regimens have little effect if the disease does not respond to platinum. However, several new therapies are emerging including bevacizumab and PARP-inhibitors, among others.
This book provides a detailed body of information important to an understanding of the clinical aspects and management of such a challenging disease. The authors strive to provide the physician with insights and illustrations as well as useful tips and tricks for the everyday clinical practice.
Several world-known experts in the field participated in this fruitful effort offering their knowledgeandeverydayexperience,aswellasvaluableandoriginalphotosfromtheirpersonal archives as well as the most recent and up-to-date guidelines in the field.
In this book, we evaluate all the challenging pathways from the moment of diagnosis to the surgical and medical therapies. The pathogenesis, the variation of the morphological types and the problems in differential diagnosis are also discussed.
Moreover, we provide an overview of recent attempts to improve the diagnosis and prognosis of ovarian cancer as well as a discussion of fertility sparing alternatives and minimal invasive (laparoscopic and robotic) approaches. All the new diagnostic and therapeutic strategies that lay out the foundation for these improvements are presented. Areas of future research are also discussed, supported by a wealth of up-to-date referenced material
The book is written at a level appropriate for both medical students, physicians as well as gynaecological oncologists, pathologists, and medical oncologists.
We hope you find this book both educational and a trusted reference as you care for your patient achieving a long “shelf life” and becoming an everyday tool of diagnosis and management
Dr. Christos Iavazzo, Metaxa Memorial Cancer Hospital, Greece
Dr. Alexandros Fotiou, Metaxa Memorial Cancer Hospital, Greece
Dr. John Spiliotis, Athens Medical Centre, Greece (Editors)
Chapter 1
Ovarian Cancer Pathology and Surgery, Historical Pearls from the Pioneering Greeks and the General Term Gynecologic Cancer to Modern Histopathology and Ovarian Malignancy
G. Tsoucalas1,*, MD, PhD
Christos Iavazzo2, MD, PhD and M. Karamanou3, MD, PhD
1Anatomy Department, Democritus University of Thrace, Alexandroupoli, Greece
2Gynecologic Oncology Department, Metaxa Cancer Hospital of Piraeus, Piraeus, Greece
3History of Medicine and Medical Deontology, Medical School of University of Crete, Heraklion, Greece
Introduction
Ovarian cancer constitutes one of the most frequently encountered cancers among female patients worldwide. Some researchers say it is the 6th fatal malignancy. For someone to comprehend such a significant pathological entity, an in-depth knowledge of all its aspects is fundamental. Medical history provides an inquiry from the point of origin in the past, when a discovery was made, up to modern times, when knowledge is perfected or at least is evolved and matured. This chapter records and presents the history of ovarian cancer, progress in the field, a summary of drugs, tools and innovative ideas from the Hellenic philosophy in antiquity until today.
During antiquity, in the Hellenic peninsula and colonies, ancient Greek medicophilosophers and physicians tried to explain cancer in a logical way. But how to rationalize such a disease that presents itself with both fatality and vanity upon confrontation. In the 5th century BC, Hippocrates (460-377 BC) and his pupils provided a rational and systemic basis to medical science a rational and systemic basis, an influential legacy of the Hippocratic approach, introducing the theory of the four humors to explain all diseases in a pathophysiological manner. According to the humoral doctrine, disease was determined as a disturbance affecting the whole person through some imbalance in the four bodily fluids, or
humors, of blood, phlegm, yellow bile, and black bile. Thus, health was defined as a balance between the body fluids (eukrasia) and external environment. If this balance was to be disturbed, the resultwas the disease itself (dyskrasia). Based mainly on humoraltheory, ancient Greek physicians developed the black bile theory of cancer, stating that an excess of the black bile in the body could provoke malignancy. It was the Hippocratic Corpus in which the terms “karkinos” (cancer) and “karkinoma” were coined, referring to the shape of a crab. The terms “phumata,” “theria,” “elkoi,” and “oidemata” all described the neoplastic nature of tumors. Tumors thus arose from a localised inflammation when flux caused an overconcentration of the black bile from the veins into the fleshy or parenchymal components of the body part, resulting in “karkinoma apertus,” the superficial type and “karkinoma occlusus,” the in-depth type of cancer. All those terms described a non-healing swelling or ulceration of a probable malignant origin. Hippocrates also introduced the term “scirrhus” to describe hard-in-substance tumorous lesions [1-3].
The Hellenic concept to clash with cancer was to operate superficial types like breast or manipulate into the cavities that is in the mouth, ear, nose, vagina and rectum. A palliative approach based mainly on herbal and mineral drugs was to follow to alleviate cancerous symptoms. Supportive measures had also been proposed to strengthen the immune system and provide a rich nourishment diet, as malignant cachexia which affected the whole body, was prevalent at the time. Postmortem examination of the human body was strictly prohibited due to social and religion reasons, instating the detailed topographic anatomy and the physiology of the internal organs somewhere in the terra incognita. Surgical intervention was limited to operations with minor (or less as possible) amputations to remove or cauterize the formations when tumors developed. A plethora of surgical tools had been manufactured by the ingenious Greek metalworkers and all were at the surgeon’s disposal alongside with gauzes, compresses, bandages, and drugs (powders, liquids, ointments, creams etc). Namely, Dioptras, hedrodiastoleus, mochliskos, ostagra, kauterion, motos moloubus, catheters, metrechytes, agkistra, tricholabis, embryoulkos, staphylagra, osteotomes, scalpels, psalis, spathomele, cyathiscomele, had been in use for operations” [4-5] all placed harmonically inside the surgeon’s medical bag, arranged in the most appropriate way, following a methodical layout, as physicians cannot keep everything in mind, as Hippocrates stated [6]. For extensive operations, Hippocrates introduced the famous Thessaly’s endemic plant, mandrake, as a general anaesthetic (it contains scopolamine), combined with morus alba and hedera, known sedatives of the era. A strict protocol of antisepsis was to be followed, performed by multiple rinses of clean boiled rainwater, firewater, salt, hot sea water (hypertonic serum), copper, tar (contains carbolic acid), resin, perfumes (myrrha, boswellia, thymus, cinnamomum, salvia, pinus, cypressus sempervirens, artemisia absinthium, aloe), milk and fire (spirit?). For less invasive operations, in the case of minor or more superficial tumors, “only a careful superficial excision and cauterization should be performed, and the wounds should be dusted with Black Hellebore plant when rot, cleaned afterwards with copper flower (an oxide) and poured with honey” to finish the therapeutic approach [2]. Dyspnoea (mostly caused by the phlegm), could sometimes have been severe, and an acute death could have occurred during an operation, or due to the tumor’s volume. In a more daring thought, to avoid such an incident, or to help the patient undertake the surgical interventions needed, Hippocrates introduced the endotracheal intubation, by using a thin pliable stannum (tin) tube through the larynx, “for the lung to attract pneuma” (pneuma ≈ air = the vital force of the soul) [2, 7]. All were there, a Greek perspective, surgical tools, palliative drugs, antiseptics and tube ventilation. The enemy was known,
understood and fatal. Its types described. Breasts, nose, ear, rectum, skin, internal organs, urinary and gynecologically. Although a notorious entity, described by various Greek scholars, surprisingly, gynecological cancer takes up little space in the treatises of ancient Greek physicians. Nonetheless, the term “gynecologic” in most works included all types - cervical, ovarian, uterine, vaginal, vulvar and fallopian, as physiology, cell, tissues and pathology were blurred at the time. Meanwhile, the term uterine in the writings of most scholars also meant gynecological and it included malignancies of the area [8].
The Hippocratics, famous for their observation and record skills, recognized both general and local pathological symptoms of gynecological malignancy. The first included cessation of menstruation, bitter taste, anorexia, pain (mild to severe), a hemorrhagic predisposition, cachexia and emaciation. Then later, the appearance of vaginal bleeding, oedema, inflammation, and ulceration. Therapeutically, Hippocrates (460-377 AD) recommended a conservative approach, applying an intravaginal enema, made of pumpkin crumb and honeycomb mixed with water. The patient was also regularly receiving laxatives and bloodlettingphlebotomiesfortheextractionofthebadhumors(mainlyblackbile)tore-balance the homeostasis of the organism, while a daily body examination was to follow. Repeated daily fumigations of the vagina, with special heated device containing dried garlic, water and seal oil was in order. In the case when the uterus felt softer in palpation, fumigations with fennel roots were applied for five or six days. For a holistic and personalized approach, every female patient was monitored, and her diet was specific. In advanced cancer stages, Hippocrates suggested that the physician should proceed with a progressive opening of the “mouth” (orifice) of the uterus with numbered waxes, and when the expansion permitted, pessaries made from rods of pine covered with oil, were to be placed as deep as it could. Having an innovative type of thinking,theHippocratessuggestedahollowleadpessarytobeinsertedinthecavity,inattempt to create an artificialvaginalopeningand topreventtheformation of adhesions.Painpalliation, care in the ulcerated area, and antiseptic were used. Hippocrates wrongfully believed that gynecological cancer was a disease of the elderly, while on the other hand realized the importance of the vascular system for the circulation of “malignant matter” (black bile). Surgical intervention was to be avoided, preserved only in small part amputations of the tumorous mass and bleeding-prevention cauterizations during the process of the lead pessary insertion. This concept dominated medical thought and for the following centuries endured as a standard-setting example of medical practice [8-9].
Aristotle (384-322 BC), the famous Greek philosopher and scientist was among the few who added some stones in the wall of gynecological cancer history after Hippocrates. In his masterpiece the “History of Animals,” described the first combined surgical removal of ovaries and uterus (hysterectomy) on animals. Although the reason for this operation was not a malignancy, Aristotle made a noteworthy observation, noting that the removal of the ovaries from the pigs had decreased their sexual appetite. Comparative anatomy and animals’ dissections provided at least some knowledge to carry out a difficult for the era surgical operation, allowing us to suppose that ancient Greek physicians had probably tried to perform removal of the uterus in an attempt to cure gynecologic carcinomas. Adequate evidence to support this hypothesis may be found in the centuries that followed [10].
Eons later, the distinguished Roman encyclopaedist Celsus (25 BC-50 AD) in his work “De Medicina” devoted a whole chapter on uterine cancer. Celsus writings were forgotten for a while, being rediscovered during the Renaissance and highly appreciated by physicians for their medical content. He mentioned, “females are subject to a malignant disease of the
womb...Sometimes this affection deprives the patient of all sensibility, in the same manner as if she falls in epilepsia. Yet with a difference, neither the eyes are turned nor does foam flow from the mouth...there is only a profound sleep.” Celsus described the anterior groin swelling, the local oedema due to the vein compression, and probably he was the first to recognize nodal metastases. To confront it he had proposed bloodletting, cataplasms, frictions and a diet free of wine, following the example of Hippocrates. He had proposed “a cerate of rose oil, or fresh hog’s lard and the whites of eggs may be mixed together and applied,” while in the case when “the womb is in pain it ought to be fumigated with Sulphur.” Still the possibility of surgical intervention was vague [11].
Soranus of Ephesus (98-138 AD), the magnificent Greek physician and gynaecologist who practiced in Rome, left us a palatial treatise on obstetrics and gynaecology. His great skills in surgical anatomy gave us a vivid delineation of the uterus, “the uterus presents sometimes withoutulcerationsometimeswithulceration.Inthiscasewemayexperiencepains,sharppains in the kidney, in the vertebrae, in umbilicus. The evolution of the disease is malignant.” He was the first who documented hysterectomy, strengthening the hypothesis that from the era of Aristotle such an operation was probably possible. Soranus believed that the “uterus should not be considered as an essentialorgan for life, notonly because it is usually prolapsed but, in some cases, it can even be cut, without death to occur... if the entire uterus is bruised (blackened), we must cut it off entirely, not only because some previously mentioned writers noticed that resection is harmless, but also because it has ceased to be a vital organ. In the case of ulcer (cancerous) from continuous prolapse and the creation of adhesion to the labia..., more preferably and most secure is to spare the uterus something from the labia as the separation cannot be accurate...in the case of a more local bruise, uterus could be excised partially.” Soranus, although a precursor in operative gynecology, was fortunate as already advanced surgical instruments, such as vaginal endoscopes (speculum-dioptras) and “kauteria” (cautery), antiseptic protocols and sedatives as well as herbal drugs were at his disposal. This was the era when surgical removal of the ovaries due to cancer originated [4, 12-13].
Galen (ca. 130-210 AD), the greatest medical authority of antiquity after Hippocrates. Although he was a great anatomist, establishing his dogma in anatomy for more than 15 centuries, he had surprisingly followed and supported the non-invasive approach of the Hippocratic school on uterine cancer. In his opinion a surgical ablation could lead to death. He had described scleroma of the uterus as a hard tumor which originated from phlegmon of the organ and which might be of long duration. Concerning the diagnosis of uterine cancer after a clinical examination, Galen wrote that “when the mouth of the womb is closed, and the neck is at the same time hard to the touch, this points to the uterus being diseased.” He had also noted that the affected women were suffering from extreme pain reflecting towards mouth cavity and lower extremities [8, 14]. Aretaeus of Cappadocia (ca. 2nd-3rd century AD) in his book “On the causes and symptoms of acute and chronic diseases,” in the chapter entitled “On uterine affections,” notably mentioned the predisposition of uterus to malignancy “the womb of the female…is conductive to many bad diseases,” recognizing the high prevalence of this type of cancer among the female population. He classified the disease into two types, the non-ulcerated and the ulcerated one, with the latter being worse in prognosis. He had masterfully recorded a vivid description, “the purulent discharge is large ...the lips of the ulcer are harsh and rough, there is certain offensive ichor, and the pain is severe. The ulcer corrodes the uterus and sometimes a loose fleshy substance protrudes which does not cicatrize for a long time but occasionsdeath...theveinsintheuterusbecomeswollenwithtensionofthesurroundingparts.”
Ovaries were known since the era of classical Greece, yet, malignancies on the area through Hellenistic and Roman periods was veiled by the term “uterine” [15-16].
Late Eastern Roman Empire (Byzantium) notions on uterine cancer were drawn directly from ancient Greek and Greco-Roman medical authorities. Uterine cancer was an incurable disease, and “black bile” is the main reason. Byzantine physicians pointed out various concepts of palliative treatment, or at least most of them [17]. Oribasius (ca. 325-403 AD) of Pergamus, was among those scholars who did not make any original contribution in the field of medicine. However, his books and the Medical Collections (Iatrikai Synagogai) are of great importance, as they contain numerous extracts fromearlier and contemporary medicalwriters, whose works could have perished forever. The work of Oribasius contains a few facts on uterine cancer. He had pointed out the painful nature of the disease and mentioned its origin from polyps and fibroids, identifying the tissue necrosis of uterine cancer. For him, gynecological cancer was incurable, while surgery could be fatal. Nonetheless, he had advocated early diagnosis and surgical excision of all endometrial tumors and opium pessaries to alleviate pain [18].
Aetius of Amida (ca. 502-575 AD) was the writer of a medical encyclopedia - the “Tetrabiblon” or “Libri Medicinales,” in 16 books. The sixteenth book of Aetius work is considered the epitome of gynecological knowledge of the Greco-Roman world, while a chapter is devoted to uterine cancer. His description includes all types of cancers in the area, “when there is no ulceration, the tumor found round the os uteri is hard and resistant to the touch, uneven, prominent, feculent in color, red or livid; sharp pains are felt in the groins, belly, vulva, and loins, and these are increased by manual examination and by various medications. Should the cancer be an ulcerated one, in addition to pain, hardness, and swelling, we find ulcers spreading and irregular, and for the most part foul, prominent, and white in color; some, however, appear feculent, livid, red and bloody.” Aetius was among those who believed malignancies of the female genital would be incurable, painful and occasionally with hemorrhage which could be worsened soon after a surgical intervention. He had suggested various drugs to alleviate both pain and hemorrhage, such as baths of fenugreek and mallow, and cataplasms of a similar kind. Paul of Aegina (ca. 625-690 AD), a century later, composed his medicalencyclopedia in seven books, named “MedicalCompendium.”Hewas alsoin favor of conservative and palliative treatment, noting that it was preferable to the surgeon to avoid the removal of the uterine cancer as there was a risk that it would grow worse. This fact probably means that he had understood the high risk of cancer cells spreading through adjacent tissues and nearby blood vessels. He recommended surgery only in cases of uterine abscesses that do not respond to medication and may provoke a fast cachexia-sepsis of the female patient [19].
None of the great Byzantine surgeons mentioned ovaries as an individual entity during cancer confrontation. All but the supreme Cleopatra Metrodora (ca. 7th century AD), a unique example of a highly educated woman physician who lived most probably around the seventh century AD, or according to some, was a contemporary of Soranus of Ephesus. Among her great number of works, “On the Uterus, Abdomen and Kidneys” contains a chapter on uterine cancer. Cleopatra Metrodora also sustained that it was a fatal and painful disease. However, he had surprisingly declared that it is of the patient’s interest to have the surgical removal of the tumor. Able to perform vaginal operations or combined hysterectomies, he had suggested that simultaneously the surgeon should surgically reconstruct the vagina and the labia and if needed to insert a tube-pesso in order for the vagina to preserve an opening. She was also fond of the
application of a tuber porridge mixed with goose fat, or a mixture of cinnamon, cob and ginger in a form of intravaginal pessary to alleviate pain and delay ulceration [20].
Theophanes Nonnus (ca. 10th century AD), originally Theophanes Chrysobalantes, a famous Byzantine physician, composed a synopsis known simply as “Synopsis” or “Epitome.” He had added nothing new, noting for the treatment of uterine cancer, that ointments and intravaginal pessaries based on mixtures of honey, wax, eggs, fat, bone marrow of several animals and birds, sheep wool, sea sponge and oxymeli (Greek: a mixture of aged sweet wines, honey=meli, raisins and fig extract) should be used to confront gynecological cancer [21]. Prominent Byzantine physicians emerged during the era of the Late Eastern Roman Empire in the lands of the Hellenic peninsula and the areas surrounding Aegean and Eastern Mediterranean seas. By compiling and refining the Hippocratic-Galenic scientific ideas they were mostly based on the knowledge acquired from their predecessors, adding only some of their own observations and clinical experience. Their work through translations and copying in monastic libraries survived the Middle Ages and contributed to the foundation of our current concepts of disease, while the Arabs soon recognized their significant role and adopted them all [17].
The contribution of Byzantine physicians to gynecological oncology was limited because of the restrictions imposed on their practice by the Church and social beliefs. The Arabs during the Late Eastern Roman Empire, through commercial and social channels, contacted scholars who were acquainted with medical knowledge of the past and soon perceived the weighty role of the ancientGreeks.Greco-Romanmedicinewasintroduced to theArabicworldbyAbuBakr Mohammad Ibn Zakariya Razi, known in the west as Rhazes (865 to 925 AD), who translated the writings of Hippocrates and Galen. A strong supporter of the “Theory of the Four Humors,” he was convinced not only that the purging of bad humors by venesection and purgatives might be curative, but also that bloodletting might be used as a preventive measure as blood itself, containing the causative material of cancer. For gynecological cancer, he noted hematuria, and supported that malignancies could not be cured by surgery and that sometimes surgery was inferior to treatment with medicinal substances, introducing the idea of chemotherapy. He is known to have often tested his chemicals in animals. Hot oil, mercurial ointments, arsenic, carbonate of lead, chicory, opium were used in cases when ulcers had been appearing in the vaginal area. Abu Marwan ibn Zuhr (1073-1162 AD), or Latinized Avenzoar was among those who practiced the dissection of animals and postmortem autopsy examinations of his patients for medical teaching according to Islamic laws. For him, anatomy was fundamental. Although he had described a case of uterine cancer (akila, gangrene), he did not perform a pelvic examination as he believed that it was a taboo, condemned by religion. Avenzoar proposed drugs and the woman died by massive bleeding. Ali Ibn al-Abbas al-Majusi (949-982 AD), Latinized asHalyAbbasAhwazi, the author of “Complete Book of the Medical Art” prescribed black myrobalan, dodder, common polypody, French lavender, nafti salt and black hellebore that should all be pulverized, pasted and then formed into a pill, introducing a per os variant. After the Islamic Empire came to an end in 1258 when the Mongols occupied Baghdad, a plethora of Arabic and Greek writings were translated into Latin by monks in monasteries and were distributed in Christian Europe [22].
The fall of the Western Roman Empire with the Church having shed the veil of conservatism slowed down the scientific evolution. However, progressively the point of progress in medical achievements shifted towards the West mainly because the conviction of importance of human autopsy weakened over time. The first medical school of Salerno, the
combined introduction of Arabic and ancient Greek medicine, the Hippocratic concept of medical ethics and the Galenic anatomic dogma, the first public dissections by Mondino de Luzzi (ca 1270-1326 AD), the firstAnatomy laboratory under JacquesDubois (1478-1555AD) in Paris and the great new society of anatomist with Andreas Vesalius (1514-1564 AD) as the greatest, boosted knowledge and surgical skills. Joseph-Claude-Anthelme Récamier (17741852) was credited for the first successful vaginal hysterectomy for cancer. The time of ovaries to emerge to the spotlight of the operating table was closer than ever before [18].
German physician Johannes Schenck von Grafenberg (1530-1598 AD) was the first modern scholar to report an ovarian malignancy in 1595. Jan Baptist van De Lamzweerde (ca 17th century) reported ovarian cysts in 1686, while Justus Theodor Schorkopff (ca 17th century) at the same period gave us the first work entirely dedicated to ovarian cysts, “De hydrope ovarii muliebris” in 1685 [23]. Scottish anatomist and obstetrician William Hunter (1718-1783) was the first to propose the removal of the ovarian cyst but did not perform it. German surgeon Johann CA Theden (1714-1797 AD) in 1771, Samuel Hartman d ‘Escher in 1807 and Ameri can physician and pioneer surgeon Ephraim McDowell (1771-1830 AD) in 1809 performed surgical removal of ovarian cysts and tumors. McDowell paved the way and Robert Lawson Tait (1845-1899 AD) who was a pioneer in pelvic and abdominal surgery became one of the most famous ovariotomists of the 19th century. French surgeon Jacques Mathieu Delpech (1777-1832 AD) was the first to introduce the hypothesis that malignant change in benign ovarian cysts may occur. Austrian gynecologist Ernst Wertheim (1864-1920 AD), a pioneer in the surgical treatment of cervical cancer in his treatise “The extended abdominal operation for carcinoma uteri,” published in 1912, had proposed a hysterectomy with removal of the ovaries American obstetrician and gynecologist Joe Vincent Meigs (1892-1963 AD) and American physician John W. Cass in 1937 documented the association of hydrothorax, ascites, and ovarian tumor commonly seen in association with ovarian fibromas (its presence also noted in ovarian cancer). Similar research was previously documented by gynecologists Otto Spiegelberg (1830-1881AD) fromGermany and Charles James Cullingworth (1841-1908 AD) from England [24].
Meigs of Boston is widely credited with the original description of the surgical approach to ovarian cancer in his 1934 landmark treatise “Tumors of the Female Pelvic Organs.” Meigs focused his career on gynecologic cancer, including malignant tumors of the ovary, despite his early observation that “the outlook for patients with this disease is hopeless.” In the third chapter of his book, he had described a consecutive series of 67 women diagnosed with “solid carcinomas” and “malignant papillary cystadenomas.” As chemotherapy had not been yet developed, he stated that surgical removal was extremely important, while the effects of X-ray application treatment had mixed results. By 1961, Meigs had refined his surgical technique, advocating for hysterectomy and bilateral salpingooophorectomy in the cases when childbearing was not of importance for the female patient. Meigs did not appreciate the minimally invasive peritoneoscope in helping to determine the diagnosis and resectability of advanced ovarian cancer, as relatively low-resolution imaging in a surface-spreading disease with wide variation in the amount and location of intraperitoneal dissemination could be obvious only after a direct inspection. His opinion has led to the reintroduction of preoperative laparoscopy. Despite intraoperative limitations for the surgeon in being unable to manually palpate and explore the abdomen, current data support the efficacy of laparoscopic or robotic interval cytoreductive surgery. Indeed, in the decades which followed and despite the original justified reverse, the value of the peritoneoscope in advanced ovarian cancer had increased.
Meigs understood that ovaries were radio-resistant and for the years to come, he insisted on surgical removal. He had noted an operative mortality rate of 1.7%, an incidence of fistulae of 9%, and a 5-year survival rate for Stage I cervical carcinoma of 74%. Meigs gained his place in history with namely the “Meigs’ radical hysterectomy,” an extended Wertheim radical hysterectomy with pelvic lymphadenectomy [25].
OutstandingGermangynaecologistsChristianGerhardLeopold(1846-1911)andFriedrich Ernst Ktukenberg (1871-1946) definite a relationship between gastric and breast cancer and ovarian malignancy [24]. Surprisingly, the ovary was found to be a striking exception to Virchow’s dictum which held that organs which were frequently the point of origin for primary cancer to be seldom involved in a secondary malignancy and vice versa [26]. Robert Meyer in 1930 was the first to write a review on ovarian cancer. He had analyzed several series of reported cases and determined that carcinoma of the ovaries could present itself as a solid or cystic structure with the latter being more common. He also noted that almost 15% of all ovarian tumors were cancerous, while 50% of those were bilateral. The second important review was conducted by Stanley Way in 1951, when he studied cases from 1930 and 1940, and quoted an incidence of 20-28% of all reported malignant tumors in females. In 1983, DL Creasman and WT Clarke-Pearson estimated in their analyses that one out of every nine females in the USA would die from ovarian malignancy. Now the ovary was exactly at the center of a fatal disease, tumors of which were needed to be classified in order to be confronted in the best way possible [24].
German gynecologist Hermann Johannes Pfannenstiel (1862-1909) introduced a classificationofovariantumorsin1898whichwastheacceptedglobalstandarduntilthe1920s. Robert Meyer was the one who amended his classification in 1915 and went on to describe granulosa celltumors, arrhenoblastoma and dysgerminoma. HCTaylor in 1929 under the terms of pathology defined three groups of ovarian cancer: i) those in which well-differentiated columnar epithelium was present; ii) tumors with glandular or papillary structure and actively malignant; and iii) tumors showing undifferentiated epithelial cells with marked nuclear changes and little or no glandular or papillary structure. In 1930, Robert Meyer proposed his classification based on primary cystic ovarian carcinomas, i) carcinoma arising in pseudomucinous cystadenoma; ii) carcinoma arising in serous cystadenoma; and iii) carcinoma arising in dermoid cysts. In the late 1970s, the World Health Organization classification of ovarian tumors became widely accepted, being present in various modified versions by many authors. In the late 1980s, the InternationalFederation of Gynaecology and Obstetrics was used as the global classification, submitted in updates. The classification was there, the pathology was known but the treatment was under study [24].
Staging the disease was fundamental for the treatment. The staging of ovarian cancer was based on thefindings duringsurgicalexploration combined withhistologicalgradeandthe type of tumor. For the proper treatment, an interdisciplinary team of expertise physicians had been proposed, including the gynecologist, pathologist, chemotherapist, and radiation expert. RW Rundles and WB Burton in 1952 were the first to report the use of alkylating agents in patients with advanced ovarian cancer and reported a favorable response in about 30% of the cases. The door of chemotherapy in modern medicine opened once more after the old Arabian concept [24]. It was in 1961 when the pioneer in medical oncology, Ezra M Greenspan (1919-2004 AD),introduced a combination of methotrexate with thiotepa [27], while in 1976 Eve Wiltshaw (1927-2008 AD) and T Kroner demonstrated the activity of cisplatin against epithelial ovarian cancer [28]. JP Smith and F Rudedge in 1975 and WT Creasman and his colleagues in 1979
suggested a triple therapy treatment. The first vincristine, actinomycin-D and cyclophosphamide, while the later methotrexate, actinomycin-D, and cyclophosphamide. Chemotherapy had been found to presentvarious disagreeable side effects includingdepression of the hematological system, gastrointestinal upset, severe nephrotoxicity and alopecia and long-termdevelopmentofmyeloblasticleukaemia.Skepticismarosebutchemotherapybecame a main modality of treatment, usually combined with surgical removal of the ovary affected. FA Pemberton in 1940 was the first after Meigs to add an innovative surgical maneuver when he advised an omenectomy, whether or not gross metastases can be seen, for 2 reasons. Omentumissooftenaffectedbymetastaticcellsandmoreover,itmaybeasourceofrecurrence in a later period. In 1971, Harrith M. Hasson pioneered an open laparoscopy for direct visualization and dissection of the tissues, an option which remained the favorite entry method for laparoscopic surgeonsin the nextdecades. In 1973,CM Bagley and his colleaguesproposed laparoscopy in the initial staging. To surgery and chemotherapy, emerged a third treatment variant, radiotherapy. During the 1950s, external radiation of the pelvis and abdomen was used as a treatment after surgery. However, studies reported that radiation was effective only when the ovarian tumor was properly debulked. The first use of radioisotopes, a novel modality in the ovarian carcinoma’s confrontation was reported by JHMuller in 1945 who used radioactive zinc as palliative therapy. A decade later, two great virologists, Scottish Alick Isaacs (19211967) and Swiss Jean Lindenmann (1924-2015) thought that immunotherapy could play a synergistic role with alkylating agenttherapyand in1957,introduced theuseof Interferon [24]. In the 21st century, taxanes as chemotherapy agents entered ovarian oncology. Despite measured improvement in survival, little additional progress has been made with conventional cytotoxic agents. Intraperitoneal therapy in standard management was introduced with mixed results. In addition, several ways of administration improvement were under study, including patient eligibility, proper catheter management, and determination of the optimal infusate. A significant advantage in progression-free and overall survival with a combination of intravenous paclitaxel and intraperitoneal cisplatin and paclitaxel was introduced. A metronomic dose studied in ovarian cancer proved to have some effect in smaller volume tumors [29]. British surgeon Thomas Spencer Wells (1818-1897) proposed in 1873 the hypothesis that ovarian cancer developed from cells on the surface of the ovary. For more than a century, physicians assumed this concept as true. However, they almost never found earlystagecancers,orevenprecursorlesions,thatwereconfinedtotheovary.In1999,LouisDubeau proposed a credible alternative innovative hypothesis. He had pointed out that ovarian tumor cells shared characteristics with healthy cells from the fallopian tubes and endometrium. He concluded that ovarian cancer therefore may arise from those tissues. Nowadays, it is widely accepted that most, if not all the most common types of ovarian cancer (high-grade serous ovarian carcinoma), arise in one of the two fallopian tubes that transport eggs from the ovaries to the uterus. According to scientists, this creates an opportunity for ovarian cancer prevention with, for example, a prophylactic removal of the tubes which may alter future cancer especially in women with a predisposition.
Conclusion
Despite the progress of medical science, ovarian cancer remains a silent killer, holding many secrets which need to be unveiled [30].
References
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[2] Hippocrates. De locis in homine & De mulierum affectibus i-iii & De natura muliebri & De fracturis & De articulis & De medico & De Visu De morbis i-iii (ed. É. Littré). Oeuvres complètes d’Hippocrate [Hippocrates of places in man & of women's affections i-iii & of woman's nature & of fractures & of joints & of physician & of sight of diseases i-iii (ed. É. Littré). Complete Works of Hippocrates]. Paris, Baillière; 1849-1853 (repr. Amsterdam: Hakkert, 1962).
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[4] Milne JS. Surgical instruments in Greek and Roman times. Oxford, USA: Clarendon Press; 1907.
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[6] Tsoucalas G, Kousoulis, AA Tsoukalas I, Androutsos G. The earliest mention of a black bag. Scand J Primary Health Care 2011;29: 196-197.
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[8] Tsoucalas G, Karamanou M, Sgantzos M, Deligeoroglou E, Androutsos G. Uterine cancer in the writings of ancient Greek physicians. J BUON 2015;20(5): 1382-1385.
[9] Kouzis A. Cancer among ancient Greek physicians. Athens: Konstantinidis; 1902 [in Greek].
[10] Aristotle. History of the Animals. Cresswell R. (transl) London: Bell; 1883.
[11] Celsus. On Medicine in eight books. Greive J (transl) London: Chidley; 1837.
[12] Karamanou M, Tsoucalas G, Creatsas G, Androutsos G. The effect of Soranus of Ephesus (98-138) on the work of midwives. Women Birth 2013;26: 226-228.
[13] Soranus. On women diseases. Athens: Kaktos; 1996 [in Greek].
[15] Tsoucalas G, Karamanou M, Laïos K, Androutsos G. Aretaeus of Cappadocia and the first accurate description of uterine carcinoma J BUON 2013;18: 805-807.
[16] Aretaeus of Cappadocia. On the causes and signs of acute and chronic disease. Reynolds TF (transl) London: Pichering; 1837.
[17] Karamanou M, Tsoucalas G, Laios K, Deligeoroglou E, Agapitos E, Androutsos G. Uterine cancer in the writings of Byzantine physicians. J BUON 2015;20(6): 1645-1648.
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Chapter 2
Ovarian Cancer Screening
Aleksandra Gentry-Maharaj*,1,2 and Aarti Sharma3
1Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK
2Department of Women’s Cancer, EGA Institute for Women’s Health, University College London, London, UK
3Department of Obstetrics and Gynaecology, University Hospital of Wales, Cardiff, UK
Introduction
We live in a society of fast evolving medicine yet advances in treatment do not always translate into improved outcomes for the sufferers. Despite numerous efforts in improving surgical approaches and introduction of a number of novel chemotherapy/targeted therapy agents, ovarian cancer remains the most lethal gynaecological cancer with the mortality rates decreasing by around 21% since the 1970s [1]. The 10-year survival rates of 35% are the worst amongst all women’s cancers [2]. As in other cancers, detecting the disease early has the most encouraging survival of over 90% if detected in Stage I, sharply declining to 13% in Stage IV [3]. The efforts have therefore focused on detecting the disease at an early stage with screening for ovarian cancer explored since the mid-1980s [4-9].
Howbesttoscreenforthediseasehasbeenandstillremainsachallenge.Duetoaprecursor lesion not being identified until recently, all efforts have focused on the detection of ovarian cancer at an early stage. In 2010, Kurman et al. proposed a unifying theory regarding the origin and pathogenesis of ovarian cancer suggesting that the disease arises in the fallopian tube or other pelvic structures prior to implanting itself on the ovary and presenting as ovarian cancer [10]. It was also suggested that there are two types of tumors, Type I tumors (low-grade serous, endometroid, clearcell, mucinous) which are thoughtto beindolent, slow growingcancers, and Type II, mainly high-grade serous cancers accounting for most of the ovarian cancer mortality [10]. The entire premise of screening for any cancer is to detect either a precursor lesion or the most aggressive cancers. Our knowledge of the precursor lesion, serous tubal intraepithelial carcinoma (STIC) [11], is very recent and despite these lesions harboring a p53 signature on the tissue level, a circulating or imaging marker for STICs is not yet available. All efforts to
date have therefore focused on the detection of early stage disease. The impetus is to detect mainly high-grade serous cancers, which account for most of ovarian cancer mortality. More recent data suggests poor outcomes in some of the other histotypes [12] which are less chemosensitive and will almost certainly recur. The focus should therefore be on detecting poorer prognostic subtypes at an earlier stage or earlier in their natural history.
The lifetime risk of ovarian cancer in the general population is ~2% [13]. This is low risk when compared to women who have a familial risk due to the inheritance of mutations in genes such as BRCA1/2, whose lifetime risk of ovarian cancer ranges from 15-40% [14]. The remit of this chapter is to focus onadvances in screening for ovarian cancer in the generalpopulation.
Keywords: ovarian cancer, screening, CA125, risk of ovarian cancer algorithm (ROCA), ultrasound, biomarkers, PLCO, UKCTOCS
Screening for Ovarian Cancer in the General Population
In the early 1980s, a transabdominal ultrasound scan approach was trialed in the King’s Study in the UK. This was a single arm ultrasound-only study of 5,479 asymptomatic women aged 18-78, screened annually for 3 years. This approach was able to detect ovarian cancer at an early stage in 5 patients (Stage IA: 4; Stage IB:1) [4].
In parallel, with the discovery of CA125 in 1981, screening strategies incorporating biomarker measurements commenced. The Stockholm study of 5,550 asymptomatic women aged >40 which was also a single arm study used the discovery of CA125 and the advancement in imaging with the introduction of transvaginal ultrasound (TVS), the latter able to provide a better view of the ovaries. Women were screened with CA125 (>35U/ml) and TVS with the study showing not only that such a contemporaneous approach can detect the disease early (primary ovarian cancer in 6 patients; Stage IA: 2, Stage IIB: 2, Stage IIIC: 2; with 20 ovarian cancers diagnosed after the end of screening) but it also demonstrated improved survival (100 months) in those detected during screening compared with 20 months for those diagnosed after screening ended [15].
A sequential approach was trialed next in the Barts pilot randomised controlled trial (RCT) of 21,935 postmenopausal women aged >45 who were screened annually with CA125 (>30U/ml) followed by TVS. The trial reported encouraging survival of 72.9 months in those in the screened group compared with 41.9 months for those in the control groupwho underwent no screening [5]. The trial introduced the multimodal approach where the screening strategy includes CA125 as a first line and TVS as a second line test.
From the mid-1980s to date, there was a large single arm transvaginal ultrasound scan (TVS) study in women over 50 years old or women over 25 years old who had a family history of ovarian cancer in Kentucky [6]. In their first report, on 25,327 asymptomatic women, the study demonstrated that the annual TVS screening detected 35 invasive ovarian cancers and 9 serous ovarian tumors with low malignant potential, suggesting that using such an approach may have detected low malignant potential tumors in a higher proportion than presented in the previousstudiesusingCA125.Thesensitivityforovariancancerwas85.0%,specificity98.7%, PPV 14.01% and NPV 99.9%. The study showed that 82% of the cancers were detected at an early stage (I/II). This finding, however, has to be taken with caution due to the lead time of screening and the single arm nature of the study. At a mean follow-up of 5.8 years, the 5-year
survival rates were higher (74.8%+/-6.6%) in the screened women compared with those treated at the same institution during the same period who were not study participants (53.7%+/-2.3%) [6].
Table 1. Summary of the performance of the different ovarian cancer screening strategies and their impact on mortality in PLCO and UKCTOCS
Study
Population size
Design
PLCO [8, 9, 16, 17]
78,215 randomised (68,557 eligible for ovarian cancer screening)
Randomised control trial with 1 screening strategy versus control group
UKCTOCS [24, 27, 28, 31, 36]
202,638 randomised (202,562 eligible for mortality analysis)
Randomised control trial with 2 screening strategies versus control group
Randomisation 1993-2003 2001-2005
Setting 10 centres in USA 13 centres in England, Wales and Northern Ireland
Age (eligibility) 55-74 50-74
Population General population (~2% risk)
Tests/strategy used
Both CA125 (using a 35U/ml cut-off) and ultrasound for 4 years, followed by CA125 alone in years 5-6
General population (~2% risk)
CA125 using the Risk of Ovarian Cancer Algorithm (ROCA) as a first line and TVS as a second line test (MMS) and Ultrasound as first and second line test (USS)
Number of annual screens 6 7 to 11
Definition of ovarian cancer Primary ovarian, tubal and peritoneal cancer
Sensitivity for detection of primary ovarian cancer
Specificity
Number of operations per cancer detected
Proportion of Early stage (I/II) disease detected by screening
86% (65% for Type II cancers)
98.4%
21.1
22.2% (screen arm) vs 21.6% (control)
Primary ovarian and tubal cancer WHO 2003 (Lancet 2016) [31] and WHO 2014 definition (Lancet 2021) [36]
36.1% (MMS) vs 23.9% Control p = 0.00013; 22.4% (USS) vs 23.9% Control p = 0.642 (Invasive ovarian/tubal cancer, Initial mortality analysis, Lancet 2016) [31]
MMS: 47.2% (95%CI 19.7-81.1) higher incidence of stage I disease and a 24.5% (–41.8 to –2.0) lower incidence of stage IV disease (Final mortality analysis on long term follow up, Lancet 2021) [36]
Mortality (initial report)8,31
Ratio 1.18 (95%CI 0.91-1.54) (Weighted log rank test)
0-14 years: MMS: 15% mortality reduction (95% CI -3 to 30; p = 0.10); USS: Mortality reduction 11% (-7 to 27; p = 0·2) Cox Proportional Hazards
0-7 years: MMS: Mortality reduction 8% (-20 to 31); USS: 2% (-27 to 26) Royston-Parmar flexible parametric model
7-14 years: MMS: Mortality reduction 23% (1-46); USS: 21% (-2 to 42) Royston-Parmar flexible parametric model
Excluding prevalent cases (0-14 years): MMS: Mortality reduction 20% (-2 to 40); 8% (-27 to 43) in 0-7 years and 28% (-3 to 49) in years 7-14
Table 1. (Continued)
Study PLCO [8, 9, 16, 17]
Median follow up (years, IQR) for initial report
Mortality (long term follow up) [9, 36]
Median follow up for long term follow up
Final impact
12.4 years (IQR 10.9-13)
Ratio 1.06 (95% CI: 0.871.30, p = 0.16) (Weighted log rank test)
14.7 years (maximum followup 19.2 years)
Stage shift not noted. No reduction in mortality
UKCTOCS [24, 27, 28, 31, 36]
11.1 years (IQR 10.0-12.0)
MMS vs control (p = 0.58 Versatile test); HR = 0·96 (0·83 to 1·10; p = 0.52) Cox Proportional Hazards
USS vs control (p = 0.36 Versatile test); HR = 0·94 (0·82 to 1·08; p = 0.37) Cox Proportional Hazards
16.3 years (IQR 15.1-17.3)
Stage shift noted. No reduction in mortality
Between 1985-1999, the Japanese Shizuoka Cohort Study of Ovarian Cancer Screening, an RCT of 82,487 postmenopausal women, set in 212 hospitals in the Shizuoka prefecture utilised an annual CA125 (>35U/ml), physical examination and TVS approach. Although a higher proportion of Stage I ovarian cancer were detected in the screened (63%) group compared with the control group (38%), this was not statistically significant [7].
In the Prostate Lung Colorectal Ovarian (PLCO) cancer screening trial, set across 10 centres in the United States, 78,286 postmenopausal women aged 55-74 years were assigned to the ovarian cancer screeningpartof the trial. The screening strategy was based on CA125 using a fixed cut-off (35U/mL) and TVS for 4 years, followed by CA125 only for a further 2 years [8]. This screening trial was initially designed to assess screening for prostate, colorectal and lung malignancies. The ovarian cancer arm was the last to be added. For this reason, 4,852 women in the screened and 4,818 in the control arm had a previous oophorectomy. The ovarian arm therefore had a total of 68,557 women randomized to screening or no screening (control arm) in a 1:1 ratio [16]. The sensitivity for the detection of ovarian cancer was 86% which decreased to 65% for the detection of Type II cancers [17]. At a median follow up of 12.4 years (10.9 -13), the trial reported no reduction in ovarian cancer mortality (ratio 1.18 95% CI 0.911.54) (Table 1). Fifteen percent (163/1080) of patients who had ‘false positive’ surgery had major complications [8]. On an extended follow up of a median of 14.7 years (maximum follow-up 19.2 years), there was no reduction in ovarian cancer mortality (ratio 1.06, 95% CI: 0.87-1.30, p = 0.16) [9]. Following the initial mortality results and the long-term follow up mortality results from this trial in 2016, the American Cancer Society [18] and the US Preventive Services Task Force (USPSTF) [19] updated their guidance that ovarian cancer screening should not be offered in the general population as it is not effective in reducing mortality from the disease. This was followed by many countries issuing a similar guidance. The largest and last trial to report, the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) was set up in 13 centres across England, Wales and Northern Ireland. The trial commenced in 2001. In total, 1,243,282 women aged 50-74 were invited and 202,638 postmenopausal women randomised to either (1) multimodal screening using annual CA125 interpreted using the Risk of Ovarian Cancer Algorithm (ROCA) (50,640) (MMS), (2) annual TVS (50,639) screening (USS) or (3) control group (101,359 women) in a 1:1:2 ratio [20].Allwomenweretoreceive6annualscreens.However,midwaythroughthetrial,ahealthy volunteer effect was observed with lower mortality from any cause [21]. At a mean of 5.55 years from randomisation, the observed all-cause mortality was 37% of that expected for the
age matched UK population [21]. The screening therefore had to be extended to 7-11 annual screens with all women screened up to 31st Dec 2011. The primary outcome was ovarian and fallopian tube cancer mortality by 31st Dec 2014. The trial also assessed acceptability, compliance, physical and psychological morbidity as well as cost-effectiveness of screening. Other than UKCTOCS, all studies and trials interpreted CA125 using a single cut-off. The MMS arm in UKCTOCS used a longitudinal algorithm to interpret CA125 [22]. The ROCA is a computerised algorithm based on the Bayes theorem which compares serial CA125 levels to patterns in cases and controls and presents the results as an estimated risk of ovarian cancer The premise of this is that women who do not have ovarian cancer have a static CA125 profile over time. However, in those developing ovarian cancer, CA125 may initially be low but then rises. It is this change that the algorithm picks up and signals that the woman is at an ‘elevated’ risk of ovarian cancer. The major challenge of this approach is that in asymptomatic women, CA125 levels are likely to be below the 35U/ml cut-off and any rise above baseline may indicate increased risk. Therefore, small rises in CA125 (e.g., 8 to 16U/ml) may mean that the woman is at an increased risk. The quality control (QC) of the CA125 assay in UKCTOCS therefore had to be run very tightly daily as even a unit change would require many women to be called back for a repeat CA125. The design of the trial with processing of all blood samples in a central laboratory closely monitored by the same team for the duration of the trial ensured tight QC and consistency when a large number of samples had to be processed daily. It must be noted that although ROCA was built using serial CA125 data from previous studies before UKCTOCS, its performance had to be assessed prospectively before it could be implemented in UKCTOCS. A pilot feasibility RCT of 13,582 postmenopausal women >50 years was therefore setup inthe mid-1990swhich showed thatfordetection of primary invasiveepithelial ovarian cancer, the ROCA-based multimodal approach to screening demonstrated a high specificity of 99.8% (95% CI, 99.7-99.9) and PPV 19% (95% CI, 4.1-45.6) [23].
The initial (prevalence) screen on UKCTOCS showed that TVS is acceptable with 48,230 of the 50,639 women randomised to the USS arm undergoing the first scan [24] despite a transvaginal approach to scanning in this older population of women. A survey of 800 women randomised to this arm showed that TVS caused very little discomfort and pain and was acceptable to the women [25]. The ultrasound arm was set up in a way that each centre was provided with the same ultrasound machine. The Quality Assurance (QA) set for the trial was further developedduring thecourse of the trial[26]. Aspostmenopausalovariescan bedifficult to visualise, an accreditation process was set up within the trial under the oversight of the UKCTOCSUltrasoundSubcommittee,appointmentofanationalleadsonographer,assessment of the scanning on the trial including visits to all centres to physically assess the scanning of all sonographers and personnel who scanned on the trial, a fail-safe monitoring approach, archiving and ongoing review of the ultrasound images by an expert. This contributed to the improvement in visualisation rate of postmenopausal ovaries at each individual centre [26]
From the initial prevalence screen data, it became apparent that the MMS strategy had higher sensitivity (89.4%) compared with USS (84.9%) for ovarian cancer overall and when restricted to invasivedisease(89.5%MMSvs75%USS) [24].Encouragingly,~50% ofcancers across both arms were detected at an early stage (I/II) [24]. During the incidence screening in the MMS arm, of the 296,911 screens, 3,329 (1.1%) women underwent clinical assessment and 640 (0.2%) underwent surgery [27]. Of these, 113 women were diagnosed with primary invasive ovarian cancer of whom 56 (50%) women had annual CA125 of under 35U/ml. Lower annual CA125 levels seemed to be associated with higher proportion of Stage I/II cancers. This
indicates that previous studies/trials would not have had the opportunity to detect these cancers as they were using a single cut off for CA125 at 30 or 35U/ml. Encouragingly, even at the incidence screening (which more likely reflects the performance of a strategy in a screening programme scenario), the MMS strategy had a sensitivity for invasive ovarian cancer of 85.8%. Over 40% (41.4%) of ovarian/tubal cancers were detected at Stage I/II [27]. The majority (81.9%) of screen detected cancers in the MMS group were Type II. Moreover, there were only 4.8 operations per case detected [27].
In the USS group, the incidence screening showed a lower sensitivity for invasive ovarian cancer of 61.5%, with a similar proportion of Stage I/II (37.5%) cancers as in the MMS arm. However, there were more operations per case detected (11) mainly due to benign ovarian neoplasms being detected in the USS butnotthe MMS arm[28, 29]. The large setof ultrasound data captured in the trial enabled exploring the risk of ovarian cancer in women across the various radiological morphologies [29, 30]. A prospective cohort study undertaken within UKCTOCS to evaluate the malignant potential of radiologically detected inclusion cysts did not show an increased risk of ovarian or other hormone dependent cancers such as breast or endometrial cancers [29]. Another prospective cohort study within the trial in the ultrasound group was undertaken to assess the absolute risk of epithelial ovarian cancers/borderline tumors/Type I and Type II tumors who had an ultrasound detected adnexal abnormality within 3 years of the initial scan. Women with adnexal abnormalities with solid elements had a 1 in 22 risk of developing epithelal ovarian cancer. The risk of borderline and Type I cancers was higher than Type II ovarian cancer where an ultrasound abnormality was detected [30].
For success of any screening programme, compliance with the strategy is essential. At the end of UKCTOCS, the compliance with both strategies was high (81% MMS vs 78% USS). The sensitivity was, as previously reported, higher in the multimodal arm (84% MMS vs 73% USS) [31]. There were very few complaints related to screen tests (2/10,000 screens in USS vs 0.86/10,000 screens MMS) despite 345,990 screens in the MMS and 327,775 screens in the USS arm (median of 8 in both) being carried out during the course of the trial. The “unnecessary” surgery undertaken in 50/10,000 screens (USS) vs 14/10,000 screens (MMS) translated to 4 operations per cancer detected in the MMS compared with 11 in the USS arm. The major complication rate in these women was 3.5% (USS) vs 3.1% (MMS) [31].
At the first UKCTOCS mortality analysis, there was a significant stage shift with 36.1% early stage (I/II) invasive ovarian cancer in the MMS arm versus 23.9% in the control arm (p = 0.00013) which was not observed in the USS arm (22.4% USS vs 23.9% control, p = 0.642). The stage shift was also significant in women with low volume (I/II/IIIa) disease (40.1% MMS vs 26% control, p < 0.0001) but not with USS screening (23.9% USS vs 26% control, p = 0.57) [31]. This was the first evidence of a stage shift in ovarian cancer screening. Compared with the control group, there was a trend towards a mortality benefit in both arms, with a 15% reductionintheMMS(p=0.10)and11%intheUSS(p=0.21)armbutthiswasnotstatistically significant.Inaddition,themortalityimpactwasonly8%inthefirst7yearsafterrandomisation but was 23% and 21% in years 7-14 post-randomisation in the MMS and USS arms, respectively (Table 1). As this was the last ovarian cancer trial to report, the unequivocal result was difficult to interpret in view of the continuing rise in the deaths in the control arm and leveling off in both the MMS and USS arms at the censorship of the 31st of December 2014.
As the mortality reduction observed in UKCTOCS was delayed in keeping with other cancer screening trials [32-36], the extent of the reduction was in line with that reported in breast cancer screening trials (15% - 25%), and the curves were separating at censorship, the
follow up was extended until the 30th of June 2020. Over time, the age-standardised incidence and mortality rates for cancer and death from any cause increased such that at the end of the trial, rates in the control arm were similar to the UK population rates [36].
Over the last 15 years, there have been major advances in our understanding of ovarian cancer, on the origins of the disease, the precursor lesion identified for the first time but also reclassification of both disease site (WHO 2014) [37, 38] and stage (FIGO 2014) [39] which all have an impact on the ability to detect the disease. Firstly, the definition of the disease changed during the course of the trial. At the time that the trial commenced, ovarian cancer was thought to arise from the ovaries where the current understanding is that the majority of highgrade serous cancers arise in the fallopian tube and involve the ovaries secondarily [10]. The previous entity of primary peritoneal cancers were re-classified as mostly high-grade serous cancer by 2020. In addition, the stage (FIGO 2014) re-classification was incorporated [36]. The Outcomes review committee reviewed all trial specific notes to ensure the final reporting of the trial was in line with the current understanding of both the disease biology and updated stage classification.
At a censorship of the 30th of June 2020, a median follow-up of 16.3 years (3.16 million women-years)andacompletefollow-upin95%ofthewomenineachgroup,thefinalmortality results of UKCTOCS showed no impact of screening on mortality from ovarian and tubal cancer (Table 1). This was observed using both the primary analysis test, the Versatile test (described in 2016, agnostic to a specific form of the screening effect and chosen following a consultation with 11 international experts) [40] and the Cox Proportional Hazards test [36].
There were 2055 women with ovarian and tubal cancer (1805 with invasive cancer) (WHO 2014classification)withanincidenceofovarianandtubalcancercomparableacrossthegroups (incidence per 100,000): 67.7 MMS, 68.2 USS and 65.4 control. The proportion of the most aggressive Type II cancers was also comparable across the groups - 79.2% MMS, 82.2% USS, 76.4% control.
The MMS strategy identified 39% more cancers at an early stage (Stage I/II), while detecting 10% fewer late-stage cancers (Stage III/IV) compared to the no screening group. There was no difference however in the incidence of early stage cancers detected in the ultrasound group compared to the no screening group [36]. The reduction in Stage III or IV disease incidence in the MMS group was not sufficient to translate into lives saved. It is therefore important to note that in screening trials, specifying cancer mortality rather than detection of early stage disease as the primary outcome is important. Based on the results of UKCTOCS, a general population screening cannot be recommended (Figure 1).
What Have We Learnt Over the Past Two Decades
Four decades of international efforts unfortunately did not have an impact on saving lives of women with ovarian cancer through screening with CA125 and ultrasound as screening tools. This may be for a number of reasons. One is that the interpretation of CA125, especially in the earlier trials, could have been improved by using a longitudinal algorithm-based approach. In UKCTOCS, the Risk of Ovarian Cancer Algorithm (ROCA) was able to detect a higher proportion of women with early stage disease in the MMS arm compared with the control arm. The novel algorithm approaches include the more recently described Methods of Mean Trends (MMT) algorithm, developed in 2015. When applied to all the CA125 data in UKCTOCS, it
showed a similar performance (at a specificity of 89.5%, sensitivity of 86.5%) to ROCA (sensitivity 87.1%; specificity 87.6%; AUC 0.915) [41]. Another reason may be that there may be a better biomarker than CA125 that could improve current strategies. Until the late 2000s, thefocushasmainlybeenonexploringtheperformanceofpromisingmarkersinthedifferential diagnosis setting – the preclinical samples from prospective studies/trials [42] had not been available until more recently [43]. The main challenge of using CA125 is its non-specific elevation in benign conditions including endometriosis. Since 2007, with the discovery of Human Epididymis HE4, efforts have been made to explore its performance both in differential diagnosis [44, 45] and more recently in screening [46, 47]. Nested case control studies from PLCO have shown that HE4 is the most promising marker after CA125 (sensitivity of CA125 of 86% vs 73% for HE4). Despite this encouraging data, the complete sample set from the MMS of UKCTOCS did not show that HE4 adds to CA125 as a first line test. The MMT algorithm, incorporating multiple markers (CA125, HE4, CA72.4, TP53 autoantibodies), showed that CA125-MMT performed the best and that HE4 added little in the detection of invasive ovarian cancer within one year of diagnosis [47]. A further reason may be that CA125 is not elevated in around 15% of ovarian cancers and therefore the current strategies do not have the capability in detecting these cancers. Data fromthe MD Anderson, AustralianOvarian CancerStudy (AOCS) and UKCTOCS demonstrated that TP53 autoantibody profile can detect 16% of the screen-negative cancers a year prior to diagnosis [48]. Therefore, a combination of the TP53 autoantibody profile with CA125 may increase the sensitivity of screening. However, UKCTOCS data showed that in ovarian cancer screening of postmenopausal women, longitudinal CA125, HE4, CA72-4 and anti-TP53 autoantibodies do not improve on the longitudinalserumCA125asafirst-linetest[47].Epigeneticprofilingmayhavearoleinaiding earlier diagnosis and aid detection of screen-negative cancers [49].
Although UKCTOCS showed that the incidence of Stage I invasive ovarian cancer was higher in the MMS group compared with the control group, this did not translate to mortality benefit. The higher mortality in Stage I disease shown in UKCTOCS may be as the MMS strategy detects the most aggressive cancers [36]. The entire premise of screening in view of our more recent understanding of the disease (over the last two decades) is to detect high-grade serous cancers (HGSC) in early stage to have an impact on mortality. However, SEER from 2019 shows that survival in Stage I HGCS is worse than in Stage III/IV HGSC [12]. This indicates that our thinking needs to change as to where in the natural history of these cancers we need to detect for screening to have an impact on mortality from the disease.
Neither UKCTOCS nor PLCO showed a mortality benefit with screening. There were differences between the two trials. In PLCO, where serum CA-125 was interpreted using an absolute cut-off, women underwent a primary screening with evaluation and follow-up of positive results at the discretion of their physicians [8, 50]. In UKCTOCS, there was central coordination of all trial activities with close monitoring of the management of screen results and further referral, longitudinal algorithm approach to interpreting CA125 and the same team of clinicians looking after the women for the duration of the trial. However, despite these differences, the stage shift with MMS screening in UKCTOCS failed to show an impact on mortality. The detailed analysis of the treatment women received across the arms may shed some light and provide an opportunity to learn lessons that could be utilised in future trials. At present, in the general population, we cannot recommend ultrasound or CA125 screening (whether as a single cut-off or using an algorithm-based approach).
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the wits of the men who are paid high salaries for detecting them. They belong to quite different spheres. If we are looking for analogies we should look up and not down.
“You wanted to know,” he said, “what was the difference between stealing and check-raising. Now, let me ask you a question. What’s the difference between check-raising and some of those big financial operations we’ve all been reading about? Suppose I have a check for five dollars, and I put my brains into it and I manipulate it so that I can pass it off for five hundred. I shove it in to the cashier and he takes it. Before he finds out his mistake, I have made myself scarce. What’s the difference between that transaction and what the ‘big fellows’ on the street are doing?” He mentioned several names that I had not thought of in that connection.
“The difference,” said I, “is—” Then it occurred to me that it was a subject to which I should give further thought. So we postponed the conversation till he should call again—which he never did.
I may be doing injustice to my friend the forger, but he gave me the impression that he considered himself to be, on the whole, a rather admirable character. His proposed change of business seemed to be rather a concession to the prejudices of the legal profession than the result of any personal scruple. As he saw himself he was a man of idealistic temper whose ideals conflicted with social usage. Society was all the time getting into his way, and in the inevitable collisions he had usually the worst of it. He regretted this, but he bore no malice. By the time a man has reached middle life and accumulated a good deal of experience he takes the world as he finds it.
He had encased himself in a moral system which was self-consistent and which explained to his own satisfaction all that had happened to him. One thing fitted into another, and there was no room for self-reproach.
Many attempts have been made to depict the character of an accomplished scamp. But Gil Blas and Roderick Random and Jonathan Wild the Great are after all seen from the outside. The author may attempt to do them justice, but there is a vein of irony that reveals a judgment of
his own. They lack the essential element of incorrigibility, which is that the scamp does not suspect himself, has not found himself out.
No novelist has ever been able to give such a portraiture of a complacent criminal as was given a century ago in the autobiography of Stephen Burroughs.
Burroughs was the son of a worthy clergyman of Hanover, New Hampshire, and from the outset was looked upon as a black sheep. As a mere boy he ran away from home and joined the army, and then with equal irresponsibility deserted. He became a ship’s surgeon, a privateersman, then a self-ordained minister, a counterfeiter, a teacher of youth, a founder of libraries, and a miscellaneous philanthropist. He was a patriot and an optimist and an enthusiastic worker in the cause of general education. He was chock-full of fine sentiment and had a gift for its expression. He enjoyed doing good, though in his own way, and never neglected any opportunity to rebuke those who he felt were in the wrong. He had a desire to reform the world, and had no doubt of the plans which he elaborated. He was capable on occasions of acts of magnanimity, which, while not appreciated by the public, gave him great pleasure in the retrospect. The intervals between his various enterprises were spent in New England jails. These experiences only deepened his love of liberty, which was one of the passions of his life.
Burroughs had a happy disposition that enabled him to get a measure of satisfaction out of all the vicissitudes of his life. He had learned neither to worry nor to repine. He was not troubled by the harsh judgments of his fellow men, for he had learned to find his happiness in the approbation of his own conscience.
He writes: “I possess an uncommon share of sensibility, and at the same time maintain an equality of mind that is uncommon, particularly in the midst of those occurrences which are calculated to wound the feelings. I have learned fortitude in the school of adversity. In draining the cup of bitterness to its dregs, I have been taught to despise the occurrences of misfortune. This one thing I fully believe, that our happiness is more in our power than is generally thought, or at least we have the ability of preventing that misery which is so common to unfortunate situations. No state or condition in life, but from which we may (if we exercise that reason which the God of Nature has given us) draw comfort and happiness. We are too apt to be governed by the opinions of others, and if they think our circumstances unhappy, to consider them so ourselves, and
of course make them so. The state of mind is the only criterion of happiness or misery.”
It was from this lofty point of view that Stephen Burroughs wrote the history of his own life. His tendency to didacticism interferes with the limpid flow of the narrative. Sometimes a whole chapter will be given over to moralizings, but the observations are never painful. They all reveal the author’s cheerful acquiescence in the inevitability of his own actions. Along with this there is the air of chastened surprise over the fact that he was made the object of persecution.
At the very beginning of the narrative one recognizes an independence which would do credit to a better man. In New England, clergymen have always been looked upon as making good ancestors, and Burroughs might have been pardoned if he had shown some family pride. From this weakness he was free. “I am,” he says, “the only son of a clergyman, living in Hanover, in the State of New Hampshire; and were any to expect merit from their parentage, I might justly look for that merit. But I am so far a Republican that I consider a man’s merit to rest entirely with himself, without any regard to family, blood, or connection.”
The accounts of the escapades of his boyhood are intermingled with dissertations on the education of youth. “I have been in the habit of educating youth for seven years, constantly; in the course of my business I have endeavored to study the operations of the human heart, that I might be able to afford that instruction which would be salutary; and in this I find one truth clearly established, viz.: a child will endeavor to be what you make him think mankind in general are.”
The neglect of this truth on the part of his parents and teachers was the cause of much annoyance to Burroughs. Throughout his life he was the innocent victim of an educational mistake. Though after a while he learned to forgive the early injustice, one can see that it rankled. He endeavored to think well of mankind in general, but it was more difficult than if he had been habituated to the exercise in infancy.
At Dartmouth young Burroughs was peculiarly unfortunate; he fell into bad company As an unkind fate would have it, his room-mate was an exemplary young man who was studying for the ministry. It appears that this misguided youth attempted to entice him into what he describes as “a sour, morose, and misanthropic line of conduct.” Nothing could have been more disastrous. “To be an inmate with such a character, you will readily conceive, no way comported with a disposition like mine, and
consequently we never enjoyed that union and harmony of feeling in our intercourse as room-mates which was necessary for the enjoyment of social life.”
To the malign influence of his priggish room-mate several misfortunes were attributed. In endeavoring to restore the moral equilibrium which had been disturbed by the too great scrupulosity of his chum, he exerted too much strength in the other direction. The result was that “a powerful triumvirate” was formed against him in the Faculty The triumvirate triumphed and his connection with Dartmouth ended suddenly.
This gave occasion to a chapter on the failure of the institutions of learning to prepare for real life. The author declares “more than one half of the time spent in the universities, according to their present establishment on this continent, is thrown away, and that my position is founded in fact I will endeavor to prove.”
I do not see how his argument is affected by the fact to which the editor calls attention in a carping footnote. “It is not strange that the author should reason in this manner. He was expelled from college in the second quarter of his second year, and in fact he studied but little while he was a member.” The editor, I fear, had a narrow mind and judged according to an academic standard which Burroughs would have despised.
From the uncongenial limitations of a college town it was a satisfaction to escape to sea. Here Burroughs’s versatility stood him in good stead. “Having no doctor engaged, I undertook to act in that capacity; and after obtaining the assistance, advice, and direction of an old practitioner, together with marks set on each parcel of medicine, I thought myself tolerably well qualified to perform the office of a physician on board the ship.”
From his seafaring life Burroughs returned with his reputation under a cloud. There were ugly rumors afloat which were readily believed by a censorious world. For once he confesses that his philosophy failed him. “I returned to my father’s house sunken and discouraged; the world appeared a gloomy chaos; the sun arose to cast a sickly glimmer on surrounding objects; the flowers of the field insulted my feelings with their gayety and splendor; the frolicsome lamb, the playful kitten, and the antic colt were beheld with those painful emotions which are beyond description. Shall all nature, shall the brute creation break out into irregular transports, by the overflowing of pleasing sensations, whilst I am shut out from even the dim rays of hope?”
Certainly not. To a mind constituted as was his there was an absurdity in the very suggestion. The brute creation should not have any monopoly of comfortable sensations, so he cheered up immediately and spent the next year loafing around his father’s house.
He had been on the coast of Africa and had taken part in some strange scenes, but his moral sense had not been blunted to such an extent that he could not grieve over some infractions of the moral law which he observed in peaceful Hanover He regretted that he had been led inadvertently by a young man named Huntington to join a party which robbed a farmer’s beehive.
“For some unaccountable reason or other, youth are carried away with false notions of right and wrong. I know, for instance, that Huntington possessed those principles of integrity that no consideration would have induced him to deprive another of any species of property, except fruit, bees, pigs, and poultry And why it is considered by youth that depriving another of these articles is less criminal than stealing any other kind of property, I cannot tell.”
Burroughs himself was inclined to take a harsher view of these transgressions than he did of some others; for example, of counterfeiting, in which he was afterwards for a time engaged during one of his brief pastorates.
The argument by which his scruples in this particular were overcome are worth repeating. The law was indeed violated in its letter, but might not a justification be found by one who interpreted it in a large spirit of charity?
“Money is of itself of consequence only as we annex to it a nominal value as the representation of property. Therefore we find the only thing necessary to make a matter valuable is to induce the world to deem it so; and let that esteem be raised by any means whatever, yet the value is the same, and no one becomes injured by receiving it at the valuation.”
The principle of fiat money having been established, the only question that remained was whether the circumstances of the times were such as to justify him in issuing the fiat. The answer was in the affirmative. “That an undue scarcity of cash now prevails is a truth too obvious for me to attempt to prove. Hence whoever contributes to increase the quantity of cash does not only himself but likewise the community an essential benefit.”
It was in his attempt to benefit the community in this way that he first experienced the ingratitude of republics, being landed in the Northampton jail.
But to see Burroughs at his best one must enter into his thoughts at that crisis in his life when he determined that his true vocation was preaching. He lingers fondly on his emotions at that period. It was at a time when he had been driven out of Hanover for conduct which had outraged the feelings of that long-suffering community
“One pistareen was all the ready cash I had on hand, and the suddenness with which I departed deprived me of the chance to raise more. Traveling on leisurely I had time for reflection.”
As was usually the case when he reflected, he grew more serene and enjoyed a frame of mind that bordered on the heroic.
“I began to look about me to see what was to be done in my present situation and to what business I could turn my attention. The practice of law, which would have been most to my mind, I could not undertake until I had spent some time in the study, which would have been attended with expense far beyond my abilities; therefore this object must be laid aside. Physic was under the same embarrassments; business in the mercantile line I could not pursue for want of capital. ... What can be done? There is one thing, said contrivance, that you can do, and it will answer your purpose—preach.”
The idea came to him as an inspiration, but immediately there was suggested an objection which to a less resourceful mind would have seemed insuperable. “What an appearance should I make in my present dress? which consisted of a light gray coat, with silver-plated buttons, green vest, and red velvet breeches.”
Down the Connecticut valley he trudged, calling to mind his father’s old sermons and gradually working himself into a state of pious rapture. The heart of no young pulpiteer beat with more appropriate emotions than his, when on the next Sunday, under an assumed name, he preached his first sermon in the village of Ludlow. “I awoke with anxious palpitation for the issue of the day. I considered this as the most important scene of my life —that, in a great measure, my future happiness or wretchedness depended on my conduct this day. The time for assembling approached! I saw the people come together. My feelings were up in arms against me,
my heart would almost leap into my mouth. What a strange thing, said I, is man! Why am I thus perturbated by these whimsical feelings!”
The moment he began the service these perturbations came to an end. Words came in a steady flow, and he felt sure that he had found his true calling in life. “No monarch when seated on a throne had more sensible feelings of prosperity than what I experienced at this time.”
The neighboring town of Pelham being without a minister, Burroughs presented himself as a candidate, and was enthusiastically accepted. He made a specialty of funeral sermons, and was soon in demand in all the surrounding country. It was at this time also that he became acquainted with the coiner who showed him how he might surreptitiously increase the amount of cash in circulation All went well till an enemy appeared who called him by name and revealed his antecedents. All Pelham was in an uproar, for the Pelhamites were “a people generally possessing violent passions, which, once disturbed, raged uncontrolled by the dictates of reason, unpolished in their manners, possessing a jealous disposition, and either very friendly or very inimical, not knowing a medium between these extremes.”
In this case they suddenly became very inimical, and Burroughs was again compelled to depart under cover of darkness. His night thoughts were always among his very best.
“Journeying on, I had time for reflection. At the dead of night—all alone— reflection would have its operation. A very singular scene have I now passed through, said I, and to what does it amount? Have I acted with propriety as a man, or have I deviated from the path of rectitude? I have had an unheard-of, disagreeable part to act; I do not feel entirely satisfied with myself in this business, and yet I do not know how I could have done otherwise, and have made the matter better. My situation has been such that I have violated the principle of veracity which we implicitly pledge ourselves to maintain towards each other, as a general thing, in society. Whether my peculiar circumstances would warrant such a line of procedure is the question. I know many things will be said in favor of it as well as against it.”
From this difficult question of casuistry he found relief in reverting to the one instance in which he had been clearly wrong, viz., joining the young men in Hanover in their raid on the farmer’s beehive. “My giving countenance to an open breach of the laws of the land in the case of the bees was a matter in which I was justly reprehensible; but that matter is
now past. I must take things as they are, and under these circumstances do the best I can. I know the world will blame me, but I wish to justify my conduct to myself, let the world think what it may.”
In this endeavor he was highly successful; and as he walked on, his spirits rose. He contrasted his own clear views with the muddled ideas of his late parishioners. “They understand the matter in the gross, that I have preached under a fictitious name and character, and consequently have roused many ideas in the minds of the people not founded on fact. Therefore they concluded from this general view the whole to be founded on wrong. The name impostor is therefore easily fixed on my character. An impostor, we generally conceive, puts on feigned appearances in order to enrich or aggrandize himself to the damage of others. That this is not the case with me in this transaction, I think is clear. That I have aimed at nothing but the bare necessaries of life, is a fact.”
Having thus cleared himself of the charge of imposture, he determined to rest his case on the broad ground of religious liberty. “That I have a good and equitable right to preach, if I choose and others choose to hear me, is a truth of which I entertain no doubt.”
When he was pursued into the borders of the town of Rutland, it was too much for his patience. “I turned and ran about twenty rods down a small hill, and the Pelhamites all after me, hallooing with all their might, ‘Stop him! stop him!’ To be pursued like a thief, an object of universal speculation to the inhabitants of Rutland, gave me very disagreeable sensations, which I determined not to bear. I therefore stopped, took up a stone, and declared that the first who should approach me I would kill on the spot. To hear such language and to see such a state of determined defiance in one whom they had lately reverenced as a clergyman struck even the people of Pelham with astonishment and fear.”
By the way, there follows a scene which makes us suspect that parts of Massachusetts in the good old days may have had a touch of “the wild West.” The two deacons who were leaders of the mob drew attention to the fact that besides having come to them under false pretenses Burroughs had absconded with five dollars that had been advanced on his salary. He owed them one sermon which was theirs of right. In the present excited state of public opinion it was obviously impossible for Burroughs to deliver the sermon, but it was suggested that he might give an equivalent. A peacemaker intervened, saying, “Wood keeps an excellent tavern hard by; I propose for all to move up there.” This proposal
was accepted by all. “I therefore came down, and we all went up towards the tavern. I called for drink, according to the orator’s advice, to the satisfaction of all.”
After that the career of Burroughs went on from bad to worse, but never was he without the inner consolations that belong to those who are misunderstood by the world. Even when he unsuccessfully sought to set fire to the jail he was full of fine sentiments borrowed from Young’s “Night Thoughts.” He quotes the whole passage beginning
Night, sable goddess! from her ebon throne.
This he seems to consider to be in some way a justification for his action. He is ever of the opinion that a man’s heart can not be wrong so long as he is able to quote poetry.
The various incarcerations to which he was subjected might only have imbittered a less magnanimous mind. They rather instilled into Burroughs a missionary spirit. He felt that he ought to take more pains to enlighten the ignorance of the world in regard to his excellent qualities. “I have many times lamented my want of patient perseverance in endeavoring to convince my persecutors of their wrong by the cool dictates of reason. Error once seen ought to be corrected. The pruning hook should never be laid aside; then we should live up to the condition of our nature, which requires a state of improving and progressing in knowledge till time shall cease.”
But even Burroughs was human. It is easier to bear great misfortunes than to meet the petty annoyances of every-day life. To one who plans his life in such a way as to depend largely on the casual gifts of strangers, their dilatoriness is often a cause of real anxiety.
Here is a painful incident which happened to him in Philadelphia. He applied to a member of Congress for a small sum of money. The gentleman was not all that he should have been. “The most striking features of his character were his great fondness for close metaphysical reasoning and a habit of great economy in his domestic concerns, and he had so long practiced upon this system that any variation from it in a person’s conduct or any want of success in a person’s undertakings were, in his view, perfectly wrong. This was the man to whom I applied as my ultimatum.”
We can see at a glance that such a man was likely to be disappointing.
“I described my circumstances to him in as clear terms as possible, and afterwards told him of the request I wished to make. Without giving me an answer either in the affirmative or the negative, he went on with a lengthy discourse to prove that my system of economy had been wrong, drawing a comparison between his prosperity and my adversity, and then pointed out a certain line of conduct that I ought then to take up and observe, and offered to assist me in prosecuting such; but as his plan had many things in it which I could not reconcile my mind to, I took the liberty of reasoning with him upon a better plan which I had marked out in my own mind.”
Upon this, the congressman became obstinate and would do nothing. His depravity came to Burroughs as a sudden shock.
“When I took a view of the world, of the pomp and splendor which surrounded crowds which perpetually passed before my eyes, to see them roll in affluence and luxury, inhabiting lofty houses, with superb equipages, and feasting upon all the delicacies of life, under these affluent circumstances withholding from me what would never have been missed from their superfluity, this brought to my mind a train of ideas that were desperate and horrid.... My eyes lighted up with indignation, my countenance was fortified with despair, my heart was swollen to that bigness which was almost too large for my breast to contain. Under this situation I arose with a tranquil horror, composedly took my hat, and politely bid Mr. Niles farewell. I believe the desperate emotions of my heart were apparently manifested to his view by my countenance; his apparent immovability relaxed, he put his hand in his pocket, and handed me three dollars. This act of kindness in a moment melted the ferocious feelings of my heart, all those desperate sensations vanished, and I found myself a man.”
Dear reader, have you not often taken a part in such a scene? When instead of handing out your dollars at once you conditioned them upon adherence to some “line of conduct,”—your conscience accuses you that you might have pointed even to the buck-saw,—do you realize what a pitiful spectacle you made of yourself?
Stephen Burroughs does not at all fulfill our preconceived notion of an habitual criminal. He did not love evil for its own sake. His crimes were incidental, and he mentions them only as the unfortunate results of
circumstances beyond his own control. His life was rather spent in the contemplation of virtue. There were some virtues which came easy to him, and he made the most of them. Like an expert prestidigitator, he kept the attention fixed on what was irrelevant, so that what was really going on passed unnoticed. He had eliminated personal responsibility from his scheme of things, and then proceeded as if nothing were lacking. He had one invariable measure for right and wrong. That was right which ministered to his own peace of body and of mind; that was wrong which did otherwise.
We are coming to see that that imperturbable egotism is the characteristic of the “criminal mind” that is least susceptible to treatment. Sins of passion are often repented of as soon as they are committed. Sins of ignorance are cured by letting in the light. Sins of weakness yield to an improved environment. But what are you going to do with the man who is incapable of seeing that he is in the wrong? Treat him with compassion, and he accepts the kindness as a tribute to his own merits; attempt to punish him, and he is a martyr; reason with him, and his controversial ardor is aroused in defense of his favorite thesis.
Sometimes the lover of humanity, after he has tried everything which he can think of to make an impression on such a character and to bring him to a realizing sense of social responsibility, becomes utterly discouraged. He feels tempted to give up trying any longer. In this he is wrong. He should not allow himself to be discouraged. Something must be done, even though nobody knows what it is.
But if the lover of humanity should give up for a time and take a rest by turning his attention to a more hopeful case, I should not be too hard on him. My Pardoner, I am sure, must have some indulgence for such a weakness.
A MAN UNDER ENCHANTMENT
ISAT down by the wayside of life like a man under enchantment.”
So Nathaniel Hawthorne wrote of his own visionary youth, and, truth to tell, the spell lasted through life.
The wayside itself was not conducive to dreams. It was a busy thoroughfare. Eager traffickers jostled one another, and there was much crying up of new wares. Many important personages went noisily along. There was a fresh interest in all sorts of good works and many improvements on the roadway. There were not many priests or Levites passing by on the other side, for ecclesiasticism was not in fashion, but there were multitudes of Good Samaritans, each one intent on his own brand-new device for universal helpfulness. There were so many of them that the poor man who fell among philanthropists often sighed for the tender mercies of the thieves. The thieves, at least, when they had done their work would let him alone. From time to time there would come groups of eager reformers, advance agents of the millennium. At last there came down the road troops hurrying to the front, and there was the distant sound of battle.
It was a stirring time, the noon of the nineteenth century; and the stir was nowhere more felt than in New England. It was a ferment of speculation, a whirl of passion, a time of great aspiration and of no mean achievement.
But if you would get a sense of all this, do not turn to the pages of Nathaniel Hawthorne. The ardor of Transcendentalism, the new spirit of reform, the war between the States,—these were noted, but they made no very vivid impression on the man who sat under enchantment. There was an interval between these happenings and his consciousness that made them seem scarcely contemporaneous.
It is a fashion in literary criticism to explain an author by his environment. With Hawthorne this method is not successful. It is not that his environment was not interesting in itself. His genius was essentially aloof. It was a plant that drew its nourishment from the air rather than from the soil. There are some men who have the happy faculty of making themselves at home wherever they happen to be. Hawthorne, wherever he had been born, would have looked upon the scene with something of a stranger’s eye. Indeed, when we think about it, the wonder is that most of us are able to take the world in such a matter-of-fact way One would suppose that we had always been here, instead of being transient guests who cannot even engage our rooms a day in advance.
It is perhaps a happy limitation which makes us to forget our slight tenure, and to feel an absolute ownership in the present moment. We are satisfied with the passing experience because it appears to us as permanent.
To the man who sat by the wayside the present moment did not stand in the sunshine sufficient unto itself. It did not appear, as it did to the man of affairs, an ultimate and satisfying reality He was not unobservant. He saw the persons passing by. But each one, in the present moment, seemed but a fugitive escaping from the past into the future. Futile flight! unavailing freedom! for in the Future the Past stands waiting for it. As he looked at each successive action it was as one who watches the moving shadow of an old deed, which now for some creature has become doom.
Did I say that Hawthorne was little influenced by his environment? It would be truer to say that the environment to which he responded was that to which most men are so strangely oblivious. He felt what another Salem mystic has expressed:
Around us ever lies the enchanted land
In marvels rich to thine own sons displayed
The true-born Yankee has always persisted, in spite of the purists, in using “I guess” as equivalent to “I think.” To his shrewd goodhumored curiosity, all thinking resolves itself into a kind of
guesswork; and one man has as good a right to his guess as another.
It is a far cry from the talk of the village store to Emerson and Hawthorne, but to these New Englanders thinking was still a kind of guessing. The observer looks at the outward show of things, which has such an air of finality, and says, “I guess there’s something behind all this. I guess it’s worth while to look into it.”
Such a mind is not deterred by the warnings of formal logic that there is “no thoroughfare.” When it leaves the public road and sees the sign “Private way, dangerous passing,” it says, “that looks interesting. I guess I’ll take that.”
And from our streets and shops and newspapers, from our laboratories and lecture rooms and bureaus of statistics, it is, after all, such a little way to the border-land of mystery, where all minds are on an equality and where the wisest can but dimly guess the riddles that are propounded.
Hawthorne belonged to no school or party. To the men of his generation he was like the minister of whom he writes who preached with a veil over his face.
Nor is his relation in thought to his ancestry more intimate than that to his contemporaries. Born to the family of New England Puritanism, we think we recognize the family likeness—and yet we are not quite sure. There are traits that suggest a spiritual changeling. When we enter into the realm of Hawthorne’s imagination we are conscious of sombre realities.
Is not this a survival of the puritanic spirit, with its brooding mysticism, its retributive predestination, its sense of the judgment to come? It was said of Carlyle that he was a Calvinist who had lost his creed. May not the same be said of Hawthorne? The old New England theology had in him become attenuated to a mere film, but through it all may we not see the old New England conscience?
Doubtless there is much of this transmitted influence. Hawthorne himself insisted upon it. Speaking of “the stern and black-browed
Puritan ancestors,” he said, “Let them scorn me as they will, strong traits of their nature have intertwined themselves with mine.”
But it is possible to exaggerate such likenesses. In Hawthorne’s case there is danger of argument in a circle. We say that there is something in Hawthorne’s imagination, in its sombre mysticism, in its brooding sense of destiny, which is like that of the spirit of the inhabitants of Salem and Boston in the old days when they walked through the narrow streets and through the shadowy woodland ways pondering the fatal sequences of life.
But how do we see these old Puritans? We see them through Hawthorne’s eyes. His imagination peoples for us the old houses. Was Hawthorne’s genius tinged with Puritanism, or are our conceptions of the Puritan character largely Hawthornesque? It is not necessary to argue this matter; it might be better to answer “Yes” to both questions.
It is the privilege of a creative genius to imprint his own features upon his forbears. It is difficult here to determine which is cause and which is effect. How marvelously Rembrandt gets the spirit of the Dutch Burgomeisters! It was fortunate for him that he had such subjects,—stalwart men with faces that caught the light so marvelously Yes, but had it not been for Rembrandt, who would have told us that these Dutch gentlemen were so picturesque?
The subject of a good artist is accurately figured; the subject of a great artist is transfigured. We cannot separate the historic reality from the transfiguring light.
But however Hawthorne may have been influenced by his Puritan inheritance, it would be hard to find one whose habitual point of view was further removed from what we are accustomed to call the “New England conscience.” It is the characteristic of that type of conscience that it has an ever-present and sometimes oppressive sense of personal responsibility. It is militant and practical rather than mystical. To it evil is not something to be endured but something to be resisted. If there is a wrong it must be righted, and with as little delay as possible.
The highest praise a Puritan could give his pastor was that he was “a painful preacher.” Jonathan Mitchell, writing of the beginnings of the church in Cambridge, says that the people of Cambridge “were a gracious, savory-spirited people, principled by Mr. Sheperd, liking an humbling, heart-breaking ministry and spirit.”
The Puritan theology was based on predestination, but the Puritan temper was not fatalistic. When that latter-day Puritan, Lyman Beecher, was expounding the doctrines of the divine decrees, one of his sons asked him, “Father, what if we are decreed to be lost?” The answer was, “Fight the decrees, my boy!”
The Calvinistic spirit was exactly opposite to the fatalistic acquiescence which shifts the responsibility from the creature to the Creator. To be sure the fall of man took place a long time ago, but we cannot say that it was none of our business. It was not an hereditary misfortune to be borne with fortitude; it was to be assumed as our personal guilt. “Original sin” means real sin. Adam sinned as the typical and representative man, and every man became a sinner. No individual could plead an alibi. The “conviction of sin” was not the acquiescence in a penalty,—it was the heartbreaking consciousness of the “exceeding sinfulness of sin.”
“In Adam’s fall we sinned all.” When they said that, they were thinking not of Adam, but of themselves. They did it; it was the guilt that was imputed to them. Sensitive consciences were tortured in the attempt fully to realize their guilt.
The real inheritors of this type of conscience were to be found among many of the radical reformers and agitators who were Hawthorne’s contemporaries and with whom he had little in common. When their formal creed had fallen off, there remained the sense of personal guilt for original sin. The sin of the nation and of the whole social order weighed heavily upon them and tortured them, and they found relief only in action.
All this was foreign to Hawthorne’s mind. In his treatment of sin there is always a sense of moral detachment. We are not made to see, as George Eliot makes us see, the struggle with temptation,—the soul,
like a wild thing, seeing the tempting bait and drawing nearer to the trap. Hawthorne begins after the deed is done. He shows us the
wild thing taken in a trap
Which sees the trapper coming thro’ the wood.
Of what is the trap made? It is made of a deed already done. Whence comes the ghostly trapper? He is no stranger in the wood. There is no staying his advance as he makes his fatal rounds.
In the preface to the “House of the Seven Gables” the author gives the argument of the story,—“the truth, namely, that the wrong-doing of one generation lives into the successive ones, and, divesting itself of every temporary advantage, becomes a pure and uncontrollable mischief.”
This is the theme of the Greek tragedy—Nemesis. The deed is done and cannot be undone; the inevitable consequences must be endured.
In the “Scarlet Letter,” when Hester and Roger Chillingworth review the past and peer into the future, Hester says, “I said but now that there can be no good event for him or thee or me who are wandering together in this gloomy maze of evil, and stumbling at every step over the guilt wherewith we have strewn our path.”
But is the present stumbling guilt or is it merely misery? The old man replies, “By the first slip awry thou didst plant the germ of evil, but since that moment it has been a dark necessity. Ye that have wronged me are not sinful, save in a kind of typical illusion, neither am I fiend-like who have snatched a fiend’s office from his hands. It is our fate. Let the black flower blossom as it may.”
Strange words to come from one who had sat in a Puritan meetinghouse! It is such comment as the Greek Chorus might make watching the unfolding of the doom of the house of Agamemnon. And when the tale of the “Scarlet Letter” has been told, how does the author himself look upon it? How does he distribute praise and blame?
“To all these shadowy beings so long our near acquaintances—as well Roger Chillingworth as his companions—we would fain be merciful. It is a curious subject of observation and inquiry whether love and hatred be not the same thing at bottom. Each in its utmost development supposes a high degree of intimacy and heartknowledge; each renders one individual dependent for his spiritual life on another; each leaves the passionate lover or the no less passionate hater forlorn and desolate by the withdrawal of its subject. Philosophically considered, therefore, the passions seem essentially the same except that one happens to be seen in celestial radiance and the other in a dusky lurid glow.” This is not the Puritan Conscience uttering itself. It is an illusive and questioning spirit.
If in his attitude toward human destiny Hawthorne was in some essential respects un-Puritan, so also was he un-modern. There is a characteristic difference between antique and modern symbols for those necessary processes, beyond the sphere of our own wills, by which our lives are determined. The ancients pictured it with austere simplicity. Life is a simple thread. The Fates spin it. It is drawn out on the distaff and cut off by the fatal shears.
Compare this with the phrase Carlyle loved to quote, “the roaring loom of Time.” Life is not a spinning-wheel, but a loom. A million shuttles fly; a million threads are inextricably interwoven. You cannot long trace the single thread; you can discern only the growing pattern. There is inevitable causation, but it is not simple but complex. The situation at the present moment is the result not of one cause but of innumerable causes, and it is in turn the cause of results that are equally incalculable. We are a part of
the web of being blindly wove
By man and beast and air and sea
Men of science show us how the whole acts upon each part and each part acts upon the whole. Modern novelists attempt, not always successfully, to give the impression of the amazing complexity of actual life, where all sorts of things are going on at the same time.
Whether we look upon it as his limitation or as his good fortune, Hawthorne adhered to the spinning-wheel rather than the loom. We see the antique Fates drawing out the thread. A long series of events follow one another from a single cause.
A part of the power of Hawthorne over our imagination lies in his singleness of purpose. In “The Marble Faun” we are told, “The stream of Miriam’s trouble kept its way through this flood of human life, and neither mingled with it nor was turned aside.”
We are made to see the dark streams that do not mingle nor turn aside, and we watch their fatal flow
But is this real, normal life? In such life do not the streams mingle? Are not evil influences quickly neutralized, as noxious germs die in the sunshine? No one would more readily acknowledge this than Hawthorne. He says: “It is not, I apprehend, a healthy kind of mental occupation to devote ourselves too exclusively to the study of individual men and women. If the person under examination be one’s self, the result is pretty certain to be diseased action of the heart almost before we can snatch a second glance. Or if we take the freedom to put a friend under the microscope, we thereby insulate him from many of his true relations, magnify his peculiarities, inevitably tear him into parts, and of course patch him clumsily together again. What wonder, then, that we be frightened at such a monster, which, after all—though we can point to every feature of his deformity in the real personage—may be said to have been created mainly by ourselves.”
The critic of Hawthorne could not describe better the limitation of his stories as pictures of real life. His characters, however clearly conceived, are insulated from many of their real relations, and their peculiarities are magnified.
In the preface to “The Scarlet Letter” he says that the tale “wears to my eye a stern and sombre aspect, too much ungladdened by the tender and familiar influences which soften almost every scene of Nature and real life, and which undoubtedly should soften every picture of them.”
One who would defend Hawthorne the Author against Hawthorne the Critic must point out the kind of literature to which his work belongs. When we judge it by the rule of the romance or of the realistic novel, we fail to do justice to its essential quality. The romancer, the storyteller pure and simple, is attracted by the swift sequence of events. His nimble fancy follows a plot as a kitten follows a string. Now it happens that in a world constituted as ours is the sequence of events follows a moral order. A good story has always in it an element of poetic justice. But the romancer does not tell his story for the sake of the moral. He professes to be as much surprised when it is discovered as is the most innocent reader. In like manner the realistic novel, in proportion as it is a faithful portrayal of life, has an ethical lesson. But the writer disclaims any purpose of teaching it. His business is to tell what the world is like. He leaves the rest to your intelligence.
But there is another kind of literature; it is essentially allegory. The allegorist takes a naked truth and clothes it with the garments of the imagination. Frequently the clothes do not fit and the poor truth wanders about awkwardly, self-conscious to the last degree. But if the artist be a genius the abstract thought becomes a person.
Hawthorne’s work is something more than allegory, but his mind worked allegorically. His characters were abstract before they became concrete. He was not a realist aiming to give a comprehensive survey of the actual world. He consciously selected the incidents and scenes which would illustrate his theme.
In his conclusion of “The Marble Faun,” when the actors have withdrawn, the Author comes before the curtain and says that he designed “the story and the characters to bear, of course, a certain relation to human nature and human life, but still to be so artfully and airily removed from our mundane sphere that some laws and proprieties of their own should be implicitly and insensibly acknowledged. The idea of the modern Faun, for example, loses all the poetry and beauty which the Author fancied in it and becomes nothing better than a grotesque absurdity if we bring it into the actual light of day.” This is not realism.
