Surgery has been the main treatment for rectal cancer for many years, however the use of radiation therapy and systemic treatment with chemotherapy, immunotherapy, and precision cancer medicines increasingly play a role for many patients. For some early stage cancers systemic therapy or surgical removal of the cancer may be all that is required. For later stage III, IV and recurrent cancer systemic treatment in addition to surgery is typically necessary.
Total Neoadjuvant Therapy
An overall treatment approach called Total Neoadjuvant Therapy (TNT) has been evolving over several years that has several advantages and is now becoming a standard of care. Neoadjuvant means “before surgery” – the delivery of neoadjuvant chemotherapy has the advantage of treating the cancer before it spreads and shrinking the cancer for more complete and easier surgical removal. Recent studies have demonstrated that TNT is associated with improved delivery of planned therapy, increased down staging, earlier introduction of optimal systemic chemotherapy, and the potential to sidestep any surgical treatment at all for many individuals with locally advanced rectal cancer.2,3,4
Results from a large multi-institutional clinical trial provide confirmatory evidence that treatment with pre-operative radiation and chemotherapy significantly decreases local cancer recurrences in patients with rectal cancer that has not spread to distant sites and should be considered the standard of care for this disease. According to the results of the phase 3 RAPIDO clinical trial released at the American Society of Clinical Oncology Annual Meeting pre-operative short-course radiation therapy (RT) followed by chemotherapy should be the new standard of care for treating locally advanced rectal cancer.2
The objective of the RAPIDO clinical trial was to determine whether a short - course of radiation therapy followed by delayed surgery, and chemotherapy administered in the waiting period, would lead to better treatment outcomes. A total of 920 patients with locally advanced rectal cancer were enrolled in the study and treated between June 2011 and June 2016. One group of patients received TNT; short course radiation followed by 6 cycles of CAPOX or 9 cycles of FOLFOX4 chemotherapy followed by surgical removal of the cancer and this was compared to “standard” therapy consisting of capecitabine-based chemo-radiotherapy and surgery.
Patients participating in this trial have now been followed in excess of 4.5 years and the 3 year probability of disease-related treatment failure is 24% in the TNT group compared to 30% in the standard treatment group. The improved outcomes were attributed to a lower rate of distant cancer spread and this resulted in a 3-year overall survival rate of 89% for those treated with TNT.1
A strategy that utilizes preoperative radiation and chemotherapy reduces the risk of local cancer recurrences in patients with rectal cancer that has not spread to distant sites.
Precision Cancer Medicines & Immunotherapy
TNT currently uses chemotherapy, but other systemic treatments including precision cancer medicines and immunotherapy can be used in the management of certain patients with rectal cancer allowing some patients to avoid surgery altogether.
Not all cancer cells are alike. They may differ from one another based on what genes have the cancer growth driving mutations. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Several precision medicines been approved for the treatment of advanced colorectal cancer or are being developed in clinical trials. In order to identify which drugs can be used your physician needs to have NGS-biomarker testing performed on the cancer tissue or blood.
Chemotherapy is any treatment involving the use of drugs to kill cancer cells. Cancer chemotherapy may consist of single drugs or combinations of drugs, and can be administered through a vein, injected into a body cavity, or delivered orally in the form of a pill. Chemotherapy is not “targeted” to the cancer and acts more generally in the body’s cells which can result in more side effects.
Immunotherapy is also a standard treatment for cancer and can be used alone or in combination with other systemic therapies. Immunotherapy either works to stimulate your immune system to attack the cancer or remove obstacles that prevent your immune system from working normally.
Checkpoint Inhibitor Immunotherapy
Checkpoint Inhibitors are precision cancer immunotherapy drugs that help to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. Programmed death (PD)-1 and PD-L1 are proteins that inhibit the bodies immune response and allow cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor blocks the PD-1 and PD-L1 pathway and restores an immune cells’ ability to recognize and fight the cancer cells.
Checkpoint inhibitors appear very effective in treating rectal cancers with mismatch repair or microsatellite instability (MSI). MSI is the condition of genetic hypermutability or a predisposition to mutations in cells that results from the bodies impaired DNA mismatch repair (MMR) mechanism. DNA MMR is an essential function and the way the body naturally corrects errors that spontaneously occur during cell division associated DNA replication. MSI and MMR can be tested for.
Surgery for Rectal Cancer
The type of operation used to remove the rectal cancer depends on the extent and location of the cancer. If the rectal cancer is located well above the anus, a low anterior resection (LAR) can be performed. This operation allows the patient to keep anal function and pass stools in a normal manner. If the rectal cancer is located close to the anus, sometimes the anus must be removed with the cancer in an operation called an abdominoperineal resection (APR). The patient must then use a colostomy bag. A colostomy is an opening where the large intestine is attached to the abdominal wall. A replaceable bag that encloses the colostomy is worn by the patient to collect stool.3-5
Low Anterior Resection Surgery (LAR)
LAR is a common treatment for rectal cancer when the cancer is located well above the anus. During a LAR, the entire rectal cancer, adjacent normal rectal tissue and surrounding lymph nodes are removed through an incision made in the lower abdomen. After the cancer is removed, the cut ends of the rectum are sewn back together. The passage of stool from the large intestine through the anus is therefore preserved. If the cancer is lower in the rectum, the cut end of the large bowel may be attached directly to the anus, a procedure known as colo-anal anastomosis. When a colo-anal anastomosis is performed, some surgeons will create a temporary colostomy in order to protect the delicate surgical connection of the large intestine to the anus. After the patient has recovered from the surgery, the temporary colostomy is removed and stool is again passed normally through the large intestine. The colon is resewn to the anus.
How Precision Medicine in Oncology Has Dramatically Changed the Way Cancer is Diagnosed and Treated
And What Patients Need to Know
Despite undergoing complete surgical removal of rectal cancer, some patients may experience recurrence of their cancer. It is important to realize that some patients with rectal cancer already have small amounts of cancer that have spread outside the rectum and were not removed by surgery. These cancer cells are referred to as micrometastases and cannot be detected with any of the currently available tests. The presence of these microscopic areas of cancer causes the relapses that follow treatment with surgery alone. External beam radiation therapy and chemotherapy can be used to cleanse the body of micrometastases in order to improve the cure rate achieved with surgical removal of the cancer.
Patients undergoing a LAR may experience lower abdominal pain after the operation. Less common complications related to surgery include bleeding, infection and temporary difficulty with emptying the bladder. Some men may experience sexual dysfunction after surgery. In-hospital death occurs after LAR in less than 5% of patients. Patients should ask their surgeon to explain the various surgical complications and their frequency of occurrence at the hospital where the surgery will be performed.
Abdominoperineal Resection Surgery (APR)
APR is a common treatment for rectal cancer when the cancer is located close to the anus. During an APR, the entire rectal cancer, adjacent normal rectum, rectal sphincter or anus, and surrounding lymph nodes are removed through an incision in the lower abdomen and the perineum (the skin around the anus). Following removal of the cancer, the incision in the perineum is sewn shut. The cut end of the large intestine is attached to an opening in the abdominal wall, called a colostomy. This opening is covered with a bag, which serves to collect stool as it passes through the large intestine and through the colostomy. In contrast to a LAR, the colostomy is permanent.
Many patients would like to avoid a permanent colostomy. When the rectal cancer lies close to the sphincter or anus, an APR is typically recommended. In some instances, a more limited surgery can be used to avoid a colostomy, or radiation therapy can be used to shrink the rectal cancer prior to surgery allowing the patient to maintain control of bowel function. Some small rectal cancers that lie close to the anus can be removed with less extensive surgery called a local excision. Not all patients can undergo a local excision (see Local Excision below).
Patients undergoing an APR may experience lower abdominal pain after the operation. Less common complications related to surgery include bleeding, infection, slow wound healing and temporary difficulty with emptying the bladder. Some men may experience sexual dysfunction after surgery. In-hospital death occurs after APR in less than 5% of patients. Patients should ask the surgeon to explain the various surgical complications and their frequency of occurrence at the hospital where the surgery will be performed.
The anal sphincter is the circular muscle that controls defecation. If damaged, patients lose control of bowel function. Sphincter-sparing treatment refers to cancer therapy that avoids removal of the anal sphincter for rectal cancers that lie close to the anus. The standard surgical procedure used to remove rectal cancer that lies close to the anus is an abdominoperineal resection (APR). Following an APR procedure, the anus is removed with the cancer, and the cut end of the large bowel is attached to the abdominal wall to form a colostomy. The colostomy is covered by a bag, which collects stool as it empties from the bowel. Because of the inconvenience of a colostomy, physicians are using sphincter-sparing treatments that allow the patient to preserve function of the anus. Sphincter-sparing treatment for rectal cancer involves limited surgery, often followed by a combination of chemotherapy and radiation therapy. The limited surgery is designed to remove the cancer and a small rim of normal bowel, but not the anus. The surgery may be performed through the anus (transanal excision) or through the coccyx (transcoccygeal) or the tailbone. A transanal excision can be performed for small cancers that lie close (within 2 inches) to the anus. Other small cancers higher in the rectum can be removed with a transcoccygeal excision.
Limited surgery can be performed to remove the cancer and preserve the anus and prevent the complications that may occur with more extensive LAR or APR surgeries. The limited surgery is designed to remove the cancer and a small rim of normal bowel, but not the anus. The surgery may be performed through the anus (transanal excision) or through the coccyx (transcoccygeal) or the tailbone. A transanal excision can be performed for small cancers that lie close (typically within 2 inches) to the anus. Other small cancers higher in the rectum can be removed with a transcoccygeal excision.
For limited surgery to be effective, the entire cancer with a rim of normal tissue must be removed. Patients with cancers that are larger, more deeply invading, or appear aggressive under the microscope are better treated with traditional surgery. In order to improve the cure rates after limited surgery alone, a combination of chemotherapy and radiation therapy is often administered for cancers that have grown into the muscular wall of the rectum.
Patients undergoing limited surgery may experience pain in the region of the perineum or tailbone. Less common complications related to surgery include bleeding, infection, and difficulty with healing of the rectal wall. In-hospital fatality is very rare after limited surgery.
Radiation Therapy for Rectal Cancer
Radiation therapy, or radiotherapy, is a common way to treat rectal cancer. Doctors who specialize in treating cancers with radiation are known as radiation oncologists. Radiation therapy involves the use of high-energy x-rays to kill cancer cells. For many rectal cancers, radiation therapy is used after surgery to destroy any cancer cells that may remain in the area of the operation. In advanced stages of rectal cancer, radiation therapy is often given before surgery to shrink the cancer, or instead of surgery when an operation cannot be performed. Radiation therapy is also commonly given in combination with anti-cancer drugs (chemotherapy). Chemotherapy has the ability to kill cancer cells directly and make radiation therapy more effective in killing cancer cells.
Radiation therapy for rectal cancer is typically given by a machine that aims x-rays at the body (external beam radiation). External beam radiation therapy (EBRT) for rectal cancer is given on an outpatient basis, 5 days a week, for approximately 5 to 6 weeks. EBRT begins with a planning session, or simulation, where marks are placed on the body and measurements are taken in order to line up the radiation beam in the correct position for each treatment. A program of daily treatments is then begun where the patient lies on a couch and is treated with radiation from multiple directions to the pelvis. The radiation oncologist may perform a second planning session or simulation near the end of treatment to focus the radiation to the area where cancer cells are most likely to remain. The last 3-5 days of treatment may be directed at this area.
Although patients do not feel anything while receiving a radiation treatment, the effects of radiation gradually build up over time. Many patients become somewhat fatigued as treatment continues. Loose stools or diarrhea are also common. Urination may become more frequent or uncomfortable. Some patients may experience loss of pubic hair or irritation of the skin. When radiation therapy is given with 5-fluorouracil chemotherapy, diarrhea can be worse. In a small percentage of patients, an obstruction or blockage in the small bowel can occur, which may require hospitalization or even abdominal surgery to relieve. Radiation therapy can also cause chronic changes in bowel function, resulting in loose stools and inflammation of the prostate when severe.
Some radiation oncology centers have special treatment equipment for certain circumstances. For small early cancers, a focused radiation beam can be aimed directly at the cancer in the rectum. Intra-operative radiation therapy (IORT) refers to treatment in a specially equipped operating room where a single dose of radiation is given during the surgery. The radiation doctor is able to see the area being treated directly and move sensitive normal structures, such as the small bowel, away from the radiation beam. IORT is usually administered when surgery is being performed for locally extensive cancer or stage II-IV cancer that has recurred in the pelvis.
Strategies to Improve Treatment for Rectal Cancer
The progress that has been made in the treatment of rectal cancer has resulted from improved surgical techniques and the development of neoadjuvant and adjuvant treatments in patients with more advanced stages of cancer and participation in clinical trials. Future progress in the treatment of rectal cancer will result from continued participation in appropriate clinical trials.
Improved Sphincter-Sparing Treatments: Because of the inconvenience of a colostomy, physicians are using sphincter-sparing treatments that allow patients with low-lying rectal cancers to keep the anus. Improved methods to select patients who can be treated with limited surgery followed by adjuvant chemotherapy and radiation therapy are being developed. More aggressive use of preoperative (neoadjuvant) chemoradiation may allow more patients with larger low-lying rectal cancers a chance to maintain anal function.
Newer Radiation Techniques: External Bean Radiation Therapy (EBRT) can be delivered more precisely to cancer-containing areas by using a special CT scan and targeting computer. This capability is known as three-dimensional conformal radiation therapy, or 3D-CRT. The use of 3D-CRT appears to reduce the chance of injury to nearby normal body structures, such as the bladder or rectum. Since 3D-CRT can better target the area of cancer, radiation oncologists are evaluating whether higher doses of radiation can be given safely with greater cancer cures.
Immunotherapy; Incorporation of precision cancer medicines and immunotherapy into treatment regiments based on NGS-biomarker testing is ongoing. Jemperli Immunotherapy
- Wiltink LM, Chen TYT, Nout RA, et al. Health-related quality of life 14 years after preoperative short-term radiotherapy and total mesorectal excision for rectal cancer: report of a multicenter randomised trial. [Eur J Cancer](https://www.ejcancer.com/article/S0959-8049(14%2900785-0/fulltext). 2014 Sep;50(14):2390–2398.
- Hospers G, Bahadoer R,Dijkstra E, et al. Short-course radiotherapy followed bychemotherapy before TME in locally advanced rectal cancer: The randomized RAPIDO trial. Presented at: the 2020 ASCO Annual Meeting; May 29-31, 2020. Abstract 4006.
- Nash GM, Weiser MR, Guillem JG et al. Long-term survival after transanal excision of T1 rectal cancer. Diseases of the Colon & Rectum. 2009;52:577-82.
- Willett CG, Compton CC, Shillito PC, et al. Selection factors for local excision or abdominoperineal resection in early stage rectal cancer.Cancer 1994;73:2716-2720.
- Jayne DG, Thorpe HC, Copeland J et al. Five-year follow-up of the Medical Research Council CLASICC trial of laparoscopically assisted versus open surgery for colorectal cancer. British Journal of Surgery. 2010;97:1638-45.