Among the three major gynecologic cancers -- cervical, endometrial, and ovarian, the number of patients with ovarian cancer, which is classified as refractory cancer, is increasing in Korea. According to the 2022 National Cancer Registration Statistics, ovarian cancer patients increased from 7.36 per 100,000 people in 2000 to 11.2 in 2020.

Ovarian cancer is marginalized in many ways due to its low incidence rate among the three major gynecologic cancers.

However, it deserves greater attention in part because of the lowest treatment performance among the three and the higher share of ovarian cancer patients among Korean women in their 40s and 50s before menopause compared to other countries.

Recently, there have been voices calling for differentiating the use of standard anticancer drugs for ovarian cancer. Against this backdrop, Korea Biomedical Review met with Professor Song Yong-sang of the Department of Obstetrics and Gynecology at Myongji Hospital to find out why. Professor Song practiced gynecologic cancer at Seoul National University Hospital for many years before moving to Myongji Hospital in Goyang, Gyeonggi Province, last year.

Ovarian cancer risk rises in proportion to the number of consistent ovulations

Question: The number of ovarian cancer patients in Korea is on the rise. What do you think is the reason for this, and what do you think the trend of ovarian cancer patients in Korea will be in the future?

Answer: If we know the reason why ovarian cancer occurs, we can presume the reason why the number of ovarian cancer patients has increased, but there is no definite answer yet. However, while the hypothesis that the cause of ovarian cancer is proportional to the number of continuous ovulations remains controversial, there is a relatively strong consensus. The more often you ovulate, the more damage you do to your ovaries. The process of repairing this damage creates an inflammatory response, an environment that can lead to cancer.

Based on the hypothesis of continuous ovulation, the age of menarche has decreased and the age of menopause has increased, meaning the number of ovulations increased. But the number of pregnancies without ovulation has decreased. Women are having fewer babies than in the past, and more women are not having children. Korean women are also less likely to use contraceptives that stop ovulation than women in other countries.

That was partly because contraceptive pills were used differently in the past, which tended to increase cancer, and Korean obstetricians and gynecologists still have reservations about them. However, current contraceptives do not have this risk and have been proven to be a cancer-preventive agent that significantly reduces the risk of ovarian cancer, so they are prescribed prophylactically to women at risk for hereditary ovarian cancer.

Cancer is a geriatric disease. Of the three major gynecologic cancers, cervical cancer is most common in women in their 40s, endometrial cancer in their 50s, and ovarian cancer in their 60s. However, in Korea, this formula does not fit well. Korea has many young ovarian cancer patients in their 40s and 50s, so we may find that ovarian cancer has a second peak after the 40s and 50s, just as cervical cancer has a second peak after the age of 70.

With data suggesting that one in two women will develop cancer in the future, it is unlikely that there will be fewer women with ovarian cancer than there are now. In addition, ovarian cancer, except for hereditary ovarian cancer, does not develop quickly. It is believed that genetic changes caused by heavy ovulation may gradually turn into cancer due to other causes. Westernized dietary habits and environmental changes are also thought to be contributing to increasing the incidence of ovarian cancer in Korea.

Q: What are the characteristics of ovarian cancer patients in Korea?

A: Ovarian cancer is not a single disease but a very complex disease. In general, ovarian cancer refers to “epithelial cell cancer.” However, women in Asia, including Korea, have a higher share of “germ cell cancer,” which occurs at a relatively young age, at about 15 percent, unlike in the West where the share of germ cell cancer is only 5 percent. Some report even a higher percentage of germ cell cancers in Asian women than 15 percent, so the number of young women with germ cell cancers is higher in the East than in the West.

In addition, if we look at epithelial cell cancers alone, the most common is serous ovarian cancer, which progresses at a very rapid rate. Ovarian cancer detected in the late stages is called serous ovarian cancer. However, the share of serous ovarian cancer is about 85 percent in Western women, while it is relatively low in Korean women, at 50-60 percent. Instead, the share of “clear cell carcinoma,” which has the worst prognosis among epithelial cell cancers, is around 15 percent in Korean women and less than 5 percent in Western women.

Taxol + platinum is uniform therapy for ovarian cancer but it’s not effective at times

There is also another characteristic. Mucinous ovarian cancer, a type of epithelial cell cancer that is large, slow-growing, and often detected in the early stages, accounts for 10-15 percent of ovarian cancer in Asian women, which is much higher than in the West. Mucinous ovarian cancer has the advantage of being detected at an early stage. However, when it is advanced, it does not respond well to the standard ovarian cancer treatment, which is a combination of Taxol Injection and platinum antineoplastic drugs. In advanced mucinous ovarian cancer, we use Taxol and carboplatin, a platinum antitumor drug, starting with an explanation that it would not work well.

Ovarian cancer is a very complicated disease divided into epithelial cell cancer subclasses and germ cell cancer subclasses, and it gets even more complex, considering the cellular differentiation of each cancer. However, people talk about ovarian cancer as if it is a single disease with the same treatment. The good news is that most ovarian cancers respond relatively well to standard anticancer drugs. However, some, including mucinous ovarian cancer and clear cell carcinoma, do not. And when ovarian cancer comes back, it's not always easy to get a good response.

This is why there is a need to differentiate the use of standard anticancer drugs in ovarian cancer. Currently, Taxol and platinum combination chemotherapy is used as a standard drug for all ovarian cancers regardless of histologic type. However, it is believed that different types of ovarian cancers respond differently to treatment, so it is necessary to use standard chemotherapy accordingly. However, this is an area that needs to be studied, and we are currently researching screening treatments for ovarian cancer.

Q: Prophylactic surgery for hereditary ovarian cancer has been covered by health insurance since 2012. How do you recommend women of childbearing age who have a gene mutation associated with ovarian cancer but do not want to receive preventive surgery for childbirth later, address their ovarian cancer risk?

A: In counseling for a BRCA1/2 gene mutation, the decision on prophylactic surgery should be made by comprehensively considering doctors’ and patients’ opinions. Currently, we recommend that women of childbearing age take birth control pills to prevent cancer and have a transvaginal sonography and blood test every four months. In the past, we used to recommend six-monthly ultrasound and blood tests. However, as hereditary ovarian cancer grows very quickly, we now recommend closer monitoring at four-month intervals.

Q: Ovarian cancer is often asymptomatic until the disease is quite advanced, so many ovarian cancer patients are diagnosed at stage 3 or 4. What is the actual stage of ovarian cancer patients in Korea at the time of diagnosis?

A: If we consider only epithelial cell cancer among ovarian cancers, Korean women are more prone to mucinous ovarian cancer, which has a high early detection rate, so the proportion of patients in stages 3 and 4 is about 55 percent. This is lower than the share of patients with stage 3 or 4 epithelial cell cancer in the West, which is 80 percent. In addition, Korea has a relatively high early diagnosis rate for ovarian cancer, with a stage 1 diagnosis rate of 25 percent and a stage 2 diagnosis rate of 20 percent.

Q: Despite a relatively high rate of early diagnosis in Korea, ovarian cancer remains one of the most difficult cancers to diagnose early. Why?

A: There is no cost-effective early detection test for ovarian cancer. Vaginal sonography can be performed to facilitate the diagnosis of ovarian cancer located deep in the pelvis, but it is less accurate than expected. In addition, tumor markers, including CA125, HE4, and CA19-9, have been proposed as blood tests but the accuracy of tumor marker tests is also quite low.

Currently, methods that can improve the accuracy of ovarian cancer diagnosis are being studied, and our research team is also researching a method for diagnosing ovarian cancer using non-coding RNA present in small cell bodies in the blood. In 2022, we published this research paper in an international journal and patented an ovarian cancer test with a sensitivity of 95 percent. However, since the market is not large and the number of patients is small, there is limited support for further research by, for instance, securing research funds to analyze the cost-effectiveness of this test in ovarian cancer.

Surgery is standard even for stage 4 ovarian cancer, as aggressive treatment contributes to improving the survival rate

Q: When ovarian cancer grows to a certain size, it is said to burst and spread cancer cells around. At what stage does this usually happen and why does it happen in ovarian cancer?

A: Most ovarian cancers are epithelial cell cancers, meaning the cancer is on the outside of the ovary. When a malignant tumor in the tissue outside of the ovary grows quickly, it is bound to burst. Usually, the malignant tumor grows from the beginning of stage 1, and if the cancer bursts, the diagnosis is made at the end of stage 1. In addition, if necrosis occurs in the burst cancer tissue, the cancerous tissue on the surface of the ovary detaches, and the detached ovarian cancer cells or tissue metastasizes along the peritoneum, which is characteristic of stage 3 or 4.

Of course, different ovarian cancers have different characteristics. Mucinous ovarian cancer grows slowly, so necrosis often does not occur and does not spread quickly. On the other hand, serous ovarian cancer, characterized by fast growth, progresses rapidly as the cancerous tissue bursts, and necrosis occurs at the end of stage 1. This is not unique to ovarian cancer. Although not as common as ovarian cancer, colorectal and stomach cancers can also rupture and spread to the peritoneum in a similar pattern.

Q: Because ovarian cancer can spread rapidly by bursting cancer cells, the cancer is removed surgically and then staged to determine future treatment options. Once staged, what is the treatment?

A: For early stage 1 ovarian cancer with good histological differentiation, surgery can end the treatment. In advanced cases, six to nine cycles of chemotherapy are given after surgery. In recent years, various methods have been tried to treat ovarian cancer, including hyperthermic anticancer chemotherapy (HIPEC) and radiofrequency therapy. Using targeted therapies, including PARP inhibitors, has increased significantly in recent years, and immuno-oncology is also a popular treatment.

With these treatments and newer adjuvant therapies, including hyperthermic chemotherapy and radiofrequency therapy, survival rates for ovarian cancer patients have improved by 5 to 10 percent over the past decade. Although aggressive treatment of ovarian cancer increases the survival period, it is important to ensure that the quality of life of patients does not decrease with treatment. In other words, we will try minimally invasive surgery and pursue precision medicine to improve survival rates while considering the patient’s quality of life.

Q: Robotic surgery for ovarian cancer is becoming more common. What are its benefits?

A: Robotic surgery allows you to perform a procedure in one step instead of the three steps required for open surgery. The device that uses the thermal energy during surgery is different, so there is less damage to normal tissue. The more expensive the device, the less heat is delivered to the normal tissue and the more normal tissue can be spared. The only clear benefit of robotic surgery that has been identified is a significant reduction in surgical complications. It is a treatment whose benefits are more about improving quality of life than reducing recurrence rates or improving survival.

Q: Surgery is the standard treatment for ovarian cancer regardless of stage, including stage 4. Why?

A: In fact, there is no strong evidence for the efficacy of surgery in ovarian cancer, but the "peculiar treatment principle of ovarian cancer" was coined because a collective analysis of past studies suggests that maximizing surgery as a local treatment may be effective. Although there are likes and dislikes of surgery, considering the effectiveness of treatment, quality of life of patients, and surgical complications, it has been established as a current trend in ovarian cancer treatment.

Currently, if stage 4 ovarian cancer responds well to upfront chemotherapy, three to four cycles of chemotherapy are followed by “'radical surgery” to remove all visible cancer, and minimally invasive surgery, including laparoscopic or robotic surgery, is used to improve patient's quality of life. Minimally invasive surgery cannot be performed in cases where the peritoneal area is bisected from the top to the bottom. In this case, an open surgery is required, but minimally invasive surgery may be possible with prior anti-cancer treatment.

In addition, patients with stage 4 ovarian cancer who have not responded to prior chemotherapy may receive one or two rounds of chemotherapy before surgery to remove the ovarian cancer. This is because removing large cancer clusters may be more effective than chemotherapy.

Q: Ovarian cancer is known to have a high recurrence rate. About 80 percent of advanced ovarian cancers recur within five years. What do you think patients can do to reduce the recurrence rate of ovarian cancer besides regular checkups?

A: Not only advanced ovarian cancer but also early-stage ovarian cancer has a recurrence rate of 20 percent in stage 1 and 40 percent in stage 2. Therefore, I recommend that patients with ovarian cancer lead a healthy lifestyle in addition to regular checkups. Exercising, eating a vegetable-based diet, and maintaining weight will also help prevent recurrence by reducing inflammation.

Recently, PARP inhibitors have been used with good results in patients screened for homologous recombination deficiency (HRD), a genetic test. Ovarian cancer has not recurred in more than six to eight years and there are no side effects. However, it is very expensive. I recommend talking to your doctor to see if you are a candidate for PARP inhibitor therapy.

Q: What would you like to say to ovarian cancer patients and their families?

A: Cancer treatment is a long-distance race. Patients with ovarian cancer often survive for a long time, so it's important to keep in mind that it's not just the patient who needs to manage their cancer survivorship but also their family. Disruption of routine can lead to family and relationship breakdown due to the patient's illness, so I hope that both the patient and the family can lead a good life, care about each other, and be consistent in their cancer treatment, just like a long-distance running.