Author:

Elisa Manacorda

Abstract

Our understanding of the mechanisms behind ovarian cancer, our ability to perform effective surgeries, and our identification of certain agents that can control the disease under specific conditions are partly thanks to the European researchers who have devoted many years of their professional lives to its diagnosis and treatment. In this article, we will explore the contributions of European research in this field and how it has evolved over the past two centuries.

Introduction

Ovarian cancer is a significant health concern, being globally the eighth most common cancer in women, accounting for an estimated 3.7% of cases and 4.7% of cancer deaths in 2020 (Webb et al 2024). Until the early 2000s, age-standardized incidence was highest in Northern Europe and North America, but this trend has changed; incidence is now declining in these regions and increasing in parts of Eastern Europe and Asia. According to Cancer Care in 2020 report by the European Federation of Pharmaceutical Industries Associations (EFPIA 2020), as of 2018, the incidence of ovarian cancer in Europe ranged from 10.6 cases per 100,000 inhabitants in Portugal to 27.5 cases per 100,000 in Latvia, with an average of 17.1 cases per 100,000 across the EU28+EFTA[1] [European Free Trade Association (EFTA) is the intergovernmental organisation of Iceland, Liechtenstein, Norway and Switzerland]

Regarding mortality, an analysis published in the Annals of Oncology shows a decline over the past decade. Predicted mortality rates in the EU are 4.3 per 100,000 (a decrease of 13%) for all ages, 1.2 per 100,000 (a decrease of 26%) for ages 20-49, 15.3 per 100,000 (a decrease of 11%) for ages 50-69, and 32.3 per 100,000 (a decrease of 11%) for ages 70-79. These favorable trends in ovarian cancer are likely to continue, largely due to the advancements in diagnosis and management (Dalmartello et al 2022).

A history of ovarian cancer discovery: from Wells to modern times

The first recorded ovarian removal surgery was performed by American physician Ephraim McDowell (1771 – 1830), who is now remembered as "the father of ovariotomy", on Christmas Day in 1809. His patient, the 46-year-old Jane Todd Crawford, initially misdiagnosed with a prolonged pregnancy, was found to have a rapidly growing ovarian tumor. Despite the lack of anesthetic and antisepsis, McDowell successfully removed the 10,2 kg (22.5-pound) tumor, making it the first successful ovarian tumor removal. Crawford recovered quickly and lived another thirty-two years (Frampton 2018).

Beyond this American primacy, Europe has significantly contributed to the development of surgical techniques in ovarian surgery. The foremost example is the British surgeon Thomas Spencer Wells (1818–1897), author of On Ovarian and Uterine Tumours: Their Diagnosis and Treatment, who, in 1882, refined ovariotomy techniques, dramatically reducing the procedure's fatality rate from 50 percent to 11 percent. Wells promoted cleanliness in surgical practices and the use of antisepsis and anesthetics, which made surgeries safer and more acceptable (Simpson 2022).

Other notable European contributors to the improvement of ovariotomy techniques included James Young Simpson and Robert Lawson Tait. Tait, a Scottish surgeon and author of Diseases of Women and Abdominal Surgery (J & A Churchill, 1889), was among the pioneers in performing successful oophorectomies. His work in the late 19th century marked considerable progress in gynecological surgery.

Further innovations in surgical procedures for ovarian cancer removal were introduced by Victor Bonney (1872–1953), a prominent British gynecological surgeon. He was influential in developing surgical techniques for removing ovarian tumors and other gynecological procedures. Bonney is primarily remembered for inventing an antiseptic solution known as "Bonney's blue," used to sterilize and stain the vagina, cervix, and surrounding skin during gynecological procedures, thereby reducing postoperative infections. He also became a pioneer in the less drastic procedure of ovarian cystectomy for removing ovarian cysts (Dally 1991).

The late 19th and early 20th centuries: refining the diagnosis

Wells' warning that all ovarian cysts had the potential to degenerate into “the worst forms of epithelial cancer” became the primary argument for immediate surgical intervention. In his gynecology textbook, Charles Reed, president of the American Medical Association, advised that all growths needed to be investigated due to the risk of “malignant degeneration” (Jasen 2009).

However, detecting the disease in its early stages was still very difficult. Symptoms of ovarian cancer were usually recognized only in retrospect and were rarely mentioned in medical literature. The non-specific symptoms of the disease were noted by Irish physician and cancer expert Walter Hayle Walshe, who remarked that the patient might first report sensations that were “merely uneasy”. For his part, Wells reported the case of a patient whose tumor had caused “incontinence of urine” for three years before she died. Reed concurred that the “symptomatology of ovarian neoplasms is sometimes very obscure,” but acknowledged that there might be “a vague sense of discomfort in the pelvis” (ibidem).

Among other European figures who provided significant insights into the historical advancements in ovarian cancer diagnosis and treatment during the late 19th and early 20th centuries is Otto von Kahlden. A German pathologist and author of Lehrbuch der Allgemeinen Pathologie für Studierende und Ärzte (G. Fischer, 1903). Kahlden made notable contributions to the classification and understanding of ovarian tumors in the early 20th century. Eduard von Siebold, a German gynecologist, also made significant contributions to the understanding and treatment of ovarian diseases, including early surgical techniques, in his work Lehrbuch der Frauenkrankheiten (Breitkopf und Härtel, 1893).

The mid-20th century: treatment developments and challenges

The mid-20th century saw significant advancements in ovarian cancer treatment. While surgery remained the primary approach, radiation therapy began to be used in some cases. Unfortunately, these treatments often had harsh side effects, and the overall prognosis for ovarian cancer remained poor.

Whole abdominal radiotherapy (WAR) was employed in the pre-chemotherapy era to sterilize large volumes of micrometastatic intraperitoneal disease. However, the low doses required to protect the bowel, kidneys, and liver were ineffective in eradicating gross residual disease in the peritoneal cavity, resulting in poor therapeutic efficacy.

Many of the toxicities of WAR in ovarian cancer were due to the large volume of tissue receiving a high dose of radiotherapy, with little sparing of the organs at risk and minimal time for intrafraction repair of normal tissues. During treatment, acute toxicities included diarrhea, fatigue, nausea, and hematologic effects. More concerning were the long-term toxicities, which included basal pneumonitis in up to 20% of patients, liver damage, and bowel toxicity (10–15% of patients). In addition to toxicity, the era of aggressive cytoreduction and effective chemotherapy (such as platinum agents) called into question the therapeutic index of radiation in the treatment of ovarian cancer (Field et al. 2017). Improved radiation techniques with lower toxicity have led to a renewed interest in the use of radiation therapy for metastatic cancers for many disease sites including ovarian cancer (ibidem). In the 1950s, the introduction of gynecological ultrasound marked a significant advancement in diagnosis. Initially used for identifying cystic and solid masses, its applications expanded to include ovarian tumors, and more. Researchers explored signs of tissue anomalies and approaches to tissue characterization. Numerous clinical conditions demonstrated the usefulness of diagnostic ultrasound in gynecology, establishing its importance in the field (Levi 1997).

The later 20th century: chemotherapy and early detection

The latter part of the 20th century saw the introduction of chemotherapy drugs specifically for ovarian cancer, such as cisplatin. Although the discovery is attributed to Rosenberg's experiments in 1965, it is important to remember that the basis of today’s most widely used family of anticancer drugs (cis-diamminedichloro-platinum (II)) was synthesized by the Italian chemist Michele Peyrone (1813–1883), born on May 26, 1813, in Mondovì Breo, a town about 60 miles south of Turin, Italy (Kauffmann et al. 2010).

Cisplatin later played a pivotal role in Alfred Werner's Nobel prize-winning research on isomerism in inorganic complexes. However, its cytostatic activity was first discovered by Barnett Rosenberg (1926-2009) and his team in 1965 while he was studying the effects of electrical fields on cell division at Michigan State University. Rosenberg initially hypothesized that electrical fields might influence cell division, inspired by the similarity between cell division patterns and iron shavings in a magnetic field. Using platinum electrodes and E. coli bacteria, he observed that the bacteria stopped dividing when an electric current was applied but grew abnormally long. When the current was stopped, normal division resumed. After two years, Rosenberg's team discovered that the actual cause was a platinum compound released from the electrodes, which was identified as cisplatin.

Intrigued by its potential as a cancer treatment, Rosenberg tested cisplatin on mice with sarcoma, finding that it significantly reduced tumors, although high doses caused kidney damage. Low doses were tolerable, and the tumors did not return after six months. Despite initial skepticism from the cancer research community, the National Cancer Institute supported further research. In 1972, NCI began funding clinical trials of cisplatin in human cancer patients. The successful outcomes of these trials led to the FDA approving cisplatin in 1978 for the treatment of testicular cancer. It was later approved for advanced ovarian and bladder cancers the same year. The patients cured by these regimens and those who benefited from the therapy number in the millions.

Subsequent research then led to the development of thousands of cisplatin analogs aimed at reducing toxic side effects, tailoring the drug to specific cancers, and combating drug resistance (NCI 2014). Notable analogs include oxaliplatin (effective against colon cancer), and carboplatin.

The latter, based on the same mechanism of action but with lower toxicity, is a result of the European research. Credit goes to Hilary Calvert, a British oncologist who has been deeply involved in anticancer drug development. The drug was synthesized and developed at the institute of Cancer Research in Sutton by Ken Harrap’s team and brought into clinical development by Hilary Calvert. Professor Eve Wiltshaw performed the first efficacy studies in recurrent ovarian cancer while Hilary Calvert developed a dosing formula based on carboplatin pharmacokinetic features, still in clinical use, which allows to adapt the dose to patient’s renal function with control of toxicity.

Early clinical studies showed that carboplatin had a very favorable safety profile in comparison to cisplatin, with reduced neurotoxicity and emetogenic potential with the same anti-tumor activity in ovarian cancer. Those characteristics led to the adoption of carboplatin by pharmaceutical companies for development and licensing. Although sporadic thrombocytopenia initially hindered its clinical uptake, this issue was resolved through a dosing formula based on renal function. The combination of carboplatin with a taxane proved particularly effective, and a randomized trial established the combination of carboplatin and paclitaxel as the standard of care for ovarian cancer (Calvert 2019).

The efficacy of carboplatin and its reduced toxicity compared to cisplatin were demonstrated in the ICON 2 and 3 studies. In the first study, a series of meta-analyses of randomized controlled trials examined whether the three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) was more or less effective than optimal-dose single-agent carboplatin for women with advanced ovarian cancer. Researchers found no evidence that CAP or carboplatin were more or less effective across different subgroups defined by age, stage, residual disease, differentiation, histology, and coordinating center. However, CAP was more toxic than carboplatin, causing more alopecia, leucopenia, and nausea. Carboplatin, on the other hand, was associated with more thrombocytopenia (ICON Collaborators 1998). ICON 3 aimed to compare the safety and efficacy of paclitaxel plus carboplatin with a control group receiving either CAP or carboplatin alone. The results showed that single-agent carboplatin and CAP are as effective as paclitaxel plus carboplatin as first-line treatments for women requiring chemotherapy for ovarian cancer. The favorable toxicity profile of single-agent carboplatin suggests that this drug is a reasonable option as first-line chemotherapy in fragile patients who can’t tolerate a combination chemotherapy (ICON Group 2002).

In addition to research on therapies, significant progress has been made in the early diagnosis of ovarian cancer, nicknamed the "silent killer." Since symptoms are often absent, identifying biochemical markers became crucial. These markers would not only aid in detecting the disease in its early stages or during recurrence, but also assess treatment response.

American oncologists Robert Bast, Robert Knapp, and their team were the first to isolate this monoclonal antibody in 1981 (Bast et al. 1981). CA-125 is a membrane glycoprotein produced by various epithelial cells. This explains its presence in the serum of patients with different tumors. The name "cancer antigen 125" originated because OC125 was the 125th antibody produced against the ovarian cancer cell line under study. Notably, the CA-125 antigen remains the only routine serum tumor marker used for diagnosing epithelial ovarian cancer (Rustin et al. 2004).

The 21st century: refining treatments and exploring new frontiers of genetics

Since the turn of the 21st century, research on ovarian cancer has advanced significantly. New chemotherapy drugs and targeted therapies that address specific molecular alterations in cancer cells have been developed. Additionally, researchers are investigating the role of genetic mutations in ovarian cancer risk, paving the way for potential preventive measures.

A key breakthrough in diagnosis, prevention and treatment came in 1990 with the identification of the BRCA1 gene by Mary King’s group at Berkeley, California, USA. The gene was named BRCA to initially reflect the place of discovery, but later came to signify breast cancer susceptibility. This American contribution was followed by the identification of the BRCA2 gene by Stratton and Wooster at the Institute of Cancer Research in London, UK. The discovery of these oncogenes marked a significant advancement in managing families with breast and ovarian cancer, enabling the introduction of risk assessment, genetic counseling, and BRCA mutational analysis.

Women who inherit a deleterious BRCA1 or BRCA2 mutation have up to a 40% and 20% lifetime risk, respectively, of developing ovarian cancer, along with higher risks of developing breast cancer. The prevalence of germline BRCA mutations in ovarian cancer was historically estimated to be around 10–15%. However, recent reports suggest that this estimate may be significantly underestimated, particularly in women with high-grade serous ovarian cancer (HGSOC).

Knowing the BRCA mutation status of a patient with ovarian cancer has become crucial for managing individual risk and identifying other family members at risk. Furthermore, a patient's BRCA1 and BRCA2 mutation status can now guide physicians and patients regarding treatment outcomes (Drew 2015).

PARP inhibitors have improved the treatment prospects for ovarian cancer in women with BRCA1 and BRCA2 mutations, they also offer promising results for women without these mutations but other dysfunctions in the DNA repair system. The first PARP enzyme was discovered in 1963, particularly through the work of researchers in Paul Mandel’s laboratory. PARP stands for poly-ADP ribose polymerase, which helps damaged cells repair themselves. As a cancer treatment, PARP inhibitors prevent PARP from performing its repair function in cancer cells, causing the cells to die. Cancer cells with BRCA gene mutations already have a compromised repair system. Therefore, blocking PARP with a PARP inhibitor prevents the cells from repairing themselves, leading to their death.

A series of drug trials led by Professors Stan Kaye and Johann de Bono at the ICR, The Royal Marsden, and Professor Jonathan Ledermann at University College in London tested the efficacy of the first PARP inhibitor olaparib as maintenance in patients with high grade serous ovarian cancers who had responded to the last previous chemotherapy with platinum and taxane. Despite previous unsuccessful chemotherapy treatments, many patients with BRCA mutation experienced strong and sustained responses with relatively mild side effects compared to conventional chemotherapy. Further trials in USA confirmed the effectiveness of PARP inhibitors in BRCA-mutated patients. By the end of 2014, olaparib was approved by both the European Medicines Agency and the US Food and Drug Administration for use in ovarian cancer patients with BRCA1 or BRCA2 mutations (NIHR 2017).

Further advancements have been made thanks to the GOG-218 (US) and ICON7 (Europe) studies. The Gynecologic Cancer InterGroup (GCIG) International Collaboration on Ovarian Neoplasms (ICON7) trial and the complementary Gynecologic Oncology Group study 0218 (GOG-0218) were designed to investigate the addition of bevacizumab to standard chemotherapy in the first-line treatment of ovarian cancer (Perren et al. 2011). Bevacizumab is a humanized monoclonal antibody that inhibits the process of angiogenesis. When added to platinum-based chemotherapy, bevacizumab did not increase overall survival in the study population as a whole but resulted in an increase of the progression free survival in both studies. However, an overall survival benefit was recorded in patients with a poor prognosis in the ICON7 study. This provides further evidence supporting the optimal use of bevacizumab in treating ovarian cancer (Oza et al. 2015).

Final remarks

With the introduction of maintenance with PARP inhibitors in first-line therapy, survival rates have improved, and today, some patients remain recurrence-free up to seven years after a first line treatment with paclitaxel and carboplatin followed by maintenance with olaparib for two years (DiSilvestro et al. 2022). This significant advancement has been made possible by several concurrent factors. Firstly, improvements in initial surgery have played a crucial role, as prognosis depends on the diameter of the residual tumor after the operation. Additionally, the choice of suitable chemotherapy, the duration of treatment with PARP inhibitors, and the characterization and selection of molecularly targeted drugs have all contributed to these excellent outcomes.

All this knowledge has been acquired through randomized multicentric studies and extensive international collaborations managed by the European Network for Gynaecological Oncological Trial groups (ENGOT), a research network of the European Society of Gynaecological Oncology. This oversight allows for the rapid enrollment of thousands of patients, avoiding the repetition of duplicate studies and conducting concurrent research, However, some obstacles remain for optimal treatment. Primarily, there is a need to understand what determines resistance to cisplatin or PARP inhibitors (Lheureux et al. 2019). It is necessary to develop drugs that can overcome this resistance and to predict which patients are more at risk of developing it. Further studies must also verify the optimal sequence of administering the drugs available today. This is to avoid exhausting the arsenal in the early stages of the clinical course also ensuring that new therapies are not introduced too late when there is no chance of response. European research networks have contributed with expertise, resources, and organization to these advancements and will undoubtedly play a fundamental role in future challenges.

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Acknowledgement

We thank Professor Cristiana Sessa, Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland for the initial guidance and final revision of the article.