Among colorectal cancer, which accounts for the second highest cancer incidence rate in Korea (11.8 percent) as of 2021, rectal cancer accounts for about 40 percent of all colorectal cancers, and is particularly difficult to treat due to its anatomical characteristics. Not only is it difficult to operate because it is located in the narrow pelvis, but it is also adjacent to major organs such as the bladder, uterus, and prostate. If the cancer progresses, it is likely to invade surrounding organs, resulting in a relatively high local recurrence rate.

Recently, total neoadjuvant therapy (TNT) and de-escalation (adjusting the intensity of adjuvant therapy after surgery) have gained attention in the treatment of rectal cancer. TNT combines chemotherapy and radiotherapy before surgery to reduce tumor size and increase the success rate of surgery. TNT has become a new hope for rectal cancer patients for whom preservation of anal and genitourinary function is important. De-escalation also replaces radiation therapy with chemotherapy to minimize side effects while maintaining therapeutic effectiveness, allowing patients to customize their treatment to their condition.

These new therapies were included in health insurance coverage in October, allowing more patients to benefit from them. This is expected to be a major turning point in overcoming the limitations of surgery and reducing recurrence rates while improving the quality of life for patients.

Korea Biomedical Review spoke to Kim Jong-gwang, professor of hematology-oncology at Kyungpook National University Chilgok Hospital, who serves as the chairman of the colorectal cancer subcommittee of the Korean Cancer Study Group (KCSG), about the possibilities and expected effects of the new rectal cancer treatments.

Question: Please explain the incidence and anatomical features of rectal cancer in Korea.

Answer: According to the 2021 National Cancer Statistics, colorectal cancer is the second most common cancer after thyroid cancer, accounting for about 11.8% of all cancers in Korea. The incidence of colorectal cancer in Korea has been steadily increasing, especially among young people under the age of 50, which is reported to be the highest in the world. Colorectal cancer is divided into colon and rectal cancer, with rectal cancer accounting for about 40% of all colorectal cancers. The rectum makes up about 15 centimeters of the total colon and, unlike colon cancer, is located within the pelvis. Due to this anatomical feature, it is difficult to secure visibility during surgery, and major organs such as the uterus in women and the prostate in men are adjacent to the bladder, so when the cancer progresses, the invasion of surrounding organs and local recurrence rates are relatively high.

Q: What are the main causes of the increasing incidence of colorectal cancer in Korea?

A: The main risk factors for colorectal cancer are excessive consumption of processed foods such as red meat, sausage, and ham, along with alcohol consumption. While the rapid westernization of dietary habits has been blamed for the recent increase, there is no clear explanation for the rise in colorectal cancer among young people. Unless these dietary issues are addressed, the frequency of colorectal cancer is expected to continue to increase or remain at current levels. Early diagnosis is on the rise, but this does not directly correlate to the actual frequency of cancer. Once rare enough to be called a “rich man's disease,” colorectal cancer has increased dramatically over the past two decades and is now the second leading cause of cancer in Korea.

Q: What is the current standard of care for rectal cancer and what are the latest treatment trends?

A: Currently, the standard treatment for locally advanced rectal cancer in Korea is surgery after concurrent chemoradiotherapy (CCRT). However, in recent years, a new treatment method, TNT, has been introduced, in which chemotherapy, which was previously administered after surgery, is administered before surgery, showing better treatment results.

In colorectal cancer surgery, the surrounding lymph nodes are also removed in consideration of the possibility of micrometastases, even if they are not visible in the picture. In the case of colon cancer, both open and laparoscopic surgeries are easy to see and the surrounding lymph nodes are relatively easy to remove, so there is almost no local recurrence, so only surgery and chemotherapy are performed.

Rectal cancer, on the other hand, is located within the pelvis, making it difficult to remove surrounding invasive tissue during surgery. As a result, local recurrence is relatively common, even with postoperative chemotherapy, so patients with advanced rectal cancer have traditionally been treated with postoperative radiation therapy. However, this method has been associated with serious side effects and sequelae due to irradiation of the normal colon. In order to reduce these side effects, preoperative CCRT was introduced in the 2000s, in which radiation therapy is administered before surgery. The anticancer drugs used in this case were used to increase the effectiveness of the radiation rather than eliminate cancer cells.

In the last two to three years, TNT has been newly introduced in the West for patients who require preoperative CCRT, in which chemotherapy (such as FOLFOX) is administered before and after CCRT. 'Total' here means that both preoperative radiation therapy and chemotherapy, which is usually administered after surgery, are administered before surgery. The RAPIDO study showed that the TNT group had better surgical outcomes and was more effective in preventing distant metastases than the standard of care (CRT followed by surgery), and TNT is now the standard of care for rectal cancer in the United States.

Q: What is the clinical significance of TNT therapy?

A: The most important goal of TNT is to reduce relapse rates. Improving cure rates with TNT is prioritized because of the high likelihood of death at recurrence. Currently, for stage 3 rectal cancer, recurrence occurs in about 30% of patients even after preoperative chemoradiotherapy (CRT), surgery, and postoperative chemotherapy, and the cure rate is significantly lowered even if additional treatment is given after recurrence. Therefore, the first step is to create an environment where the chemotherapy scheduled for postoperative treatment can be administered before surgery. Radiation therapy can then be omitted if the MRI shows a good response.

The rate of pathologic complete remission (pCR) is significantly increased in patients treated with TNT, which leads to a decrease in the recurrence rate. In particular, for T4 patients with bladder involvement, TNT treatment has been able to shrink the cancer and avoid bladder resection. In the past, these patients faced insurance cutbacks, but now they can be treated with radiation, chemotherapy, and surgery, which has significantly improved outcomes.

Q: TNT reimbursement has increased access to treatment, but which patients can benefit and what are the eligibility criteria?

A: Prior to TNT reimbursement, the standard of care for patients with stage 2 or higher rectal cancer was CRT followed by surgery. High-risk patients with deeply invasive (T4) cancer, high carcinoembryonic antigen (CEA) levels, or potential for metastasis, especially in stage 3, needed TNT, but reimbursement made it difficult to access outside of clinical studies.

With a high proportion of all rectal cancer patients being stage 3, it is estimated that more than half of all rectal cancer patients could benefit from TNT. With conventional treatments, high-risk patients' cancers can progress during the six to eight weeks following CRT while they wait for the radiation to take effect, but TNT allows chemotherapy to be administered during this time. The total number of chemotherapy treatments is similar, but the advantage of administering chemotherapy before surgery is that it reduces the need for postoperative chemotherapy.

Overseas, the U.S. National Comprehensive Cancer Network (NCCN) guidelines recommend TNT for patients with stage 2 or higher and T3 or higher, and the European Society for Medical Oncology (ESMO) guidelines recommend TNT for patients with deep invasion such as T4 in stage 2 or 3. In Korea, TNT has recently been reimbursed, and although there are no specific guidelines yet, it is expected that the application of TNT will be expanded, focusing on stage 3 (T4) patients with a high risk of recurrence, patients with high CEA levels, and younger rectal cancer patients.

Q: What treatment strategy is de-escalation, which is covered by insurance together with TNT?

A: Although radiation side effects are much better nowadays, when patients with rectal cancer receive concurrent chemoradiotherapy, young women often have their ovaries moved to the side to reduce the chance of infertility. For men, sperm can be frozen, but sexual function may be affected.

Younger patients with stage 2 or higher with a good prognosis may undergo de-escalation, in which chemotherapy is given before surgery instead of after, and if they respond well, surgery is performed immediately. This avoids radiation therapy and preserves organ function. In general, about 80 percent of stage 2 and 3 patients with a good prognosis respond well to preoperative chemotherapy and can avoid radiation therapy.

If the cancer has not shrunk enough on MRI after prior chemotherapy, radiation therapy may be given at that time. Patients whose cancer has shrunk by 20 percent with chemotherapy may have similar outcomes without radiation. This diversity of treatment options allows for personalized treatment for each patient.

Q: What is the status of new drug development for metastatic rectal cancer?

A: There are a number of new drugs in development for the treatment of metastatic rectal cancer, some of which are covered by insurance. However, there are still many agents that are not yet covered by insurance, and ongoing reimbursement efforts are needed.

Of particular note is the immuno-oncology drug dostarlimumab for the MSI-HIGH (Microsatellite Instability-High) group, which accounts for 10-15 percent of rectal cancer patients. It is of interest because it has shown a high response rate and may be able to be treated without surgery. It is already available in the U.S. but is still in the approval process in Korea.

Q: What is your message to patients about the prevention and treatment of rectal cancer?

A: If you are over 50 years old, I recommend regular endoscopic screening for early detection of rectal cancer. Korea has a well-equipped screening environment, excellent screening capabilities, and reasonable costs.

For patients diagnosed with rectal cancer, I would like to share some hopeful news. In the past, permanent ostomy was inevitable in most cases of lower rectal cancer due to difficulty in securing safety margins, but in recent years, the rate of permanent ostomy has decreased significantly due to advances in chemotherapy and radiotherapy. In addition, the cure rate has improved with the newly reimbursed TNT, and organ function can be preserved through de-escalation strategies in some cases. Therefore, if you receive proper treatment at a specialized medical center, you can expect a high cure rate, so please do not worry too much.