Heather Stringer

"The doctor briefly touched on one or two complications, but nothing about the risk of infection."

When Nancy Tellez, 37, received a cervical cancer diagnosis in 2019, her oncologist was confident the surgery to treat the cancer would have no complications because Tellez was young and healthy.

Her cervix, uterus and a portion of her vagina were removed during a radical hysterectomy, and she was told to expect some discomfort during recovery after discharge from the hospital.

The pain in her pelvis worsened when she returned home, but Tellez, of Topeka, Kansas, assumed the throbbing was normal after surgery. During the following four days, her right pelvis became swollen, fluid started leaking out of her vagina and her level of discomfort surpassed labor pains. She also had a temperature of 104 degrees.

A friend rushed Tellez to the emergency room, where a CT scan showed a mass in her pelvis. During a second surgery, doctors drained the abscess.

The last thing Tellez remembered that day was shaking because she felt extremely cold in the recovery room, and then she lost consciousness.

She went into septic shock due to an infection, and she awoke briefly at one point as a priest was reading her last rites. Tellez was treated with antibiotics and regained consciousness several days later, when doctors explained that she was lucky to be alive.


The infection was likely caused by urine leaking from a tear in her urethra. She also developed Clostridioides difficile (an infection commonly known as C. diff that can cause severe diarrhea and inflammation of the colon) while in the hospital, possibly as a result of the antibiotics.

Although Tellez eventually recovered and is grateful that her cancer is in remission, she wishes she had understood the risk of infection before undergoing surgery.

“The doctor briefly touched on one or two potential complications, but nothing about the risk of infection,” she says. “I had so many medical bills related to the complications, and I was going through a divorce and raising four children.”

Surgery is a part of treatment for many patients diagnosed with gynecologic cancer, which includes uterine, ovarian, cervical, vaginal and vulvar cancers.

“Infections after surgery are a problem in the United States and worldwide,” says Dr. Oliver Zivanovic, director of innovative surgical technology at Memorial Sloan Kettering Cancer Center in New York City. “I’m taking care of patients with gynecologic cancer who are already suffering from a complex disease, and it’s important to try to minimize the risk of infections for these patients.”

The surgeries range from laparotomy — a large incision in the abdomen — to minimally invasive procedures such as a laparoscopy (use of a thin, lit tube with a video camera administered via a small incision) or robotic approaches to vulvar and vaginal procedures involving removal of tissue in a localized area. 

The risk of infection is lower with early-stage disease that can be treated with minimally invasive surgery, but women with advanced cancer are usually not candidates for laparoscopic or robotic procedures, says Zivanovic.

“I see many older patients who present with metastatic ovarian or uterine cancer who require large incisions, long operative times and blood transfusions, and all these factors increase the risk of infection,” he says.

Studies have shown that patients with gynecologic cancer who require a bowel resection (the removal of some or all of the large intestine) during surgery are at highest risk of surgical site infection (SSI), with rates ranging from 33% to 37% in recent studies. Patients may also have comorbidities, such as poorly controlled diabetes, obesity or compromised immune systems, that can elevate the chance of developing an infection, according to Zivanovic.

Infections may increase the length of stay in the hospital and the chance of needing additional interventions such as a repeat surgical procedure — and elevate the risk of death by as much as elevenfold.

Although infection after surgery is a complex problem, researchers are exploring strategies to reduce the risk of this complication.

“In gynecologic oncology, many researchers and surgeons are working to discover ways to make surgery safer,” says Dr. Amanda Nickles Fader, a professor of gynecology/obstetrics and oncology and vice chair of gynecologic surgical operations at Johns Hopkins Health System in Baltimore. “These strategies help patients experience a better recovery and transition more quickly to further cancer treatments, if needed.”

Nickles Fader and colleagues previously studied the outcomes of more than 200 women who underwent cytoreductive surgery (a procedure to remove tumors in the abdominal cavity) for ovarian cancer, and the results demonstrated that a “bundle” of infection prevention strategies reduced SSIs from 20% to 3%, and the hospital readmission rate dropped from 13% to 3%.

The strategies included the use of a sterilizing soap known as chlorhexidine, which the patients applied at home before surgery and the medical team used during the surgery.

Patients in the bundle group also received antibiotics prior to surgery, and those requiring bowel resection were prescribed laxatives the night before to clear the colon. During especially prolonged surgeries, patients received antibiotics during the procedure, and those undergoing colon resection received broader-spectrum antibiotics that acted on a wider range of bacterial types.

“Communication between the surgery, anesthesiology and nursing teams is critical during surgery to keep the patient safe,” explains Nickles Fader.

Before closing abdominal incisions in patients who underwent colon resection, the operating team changed gloves, gowns and medical instruments to avoid using surgical tools that could be contaminated with bacteria from the colon. In surgeries involving colon resection, these safety measures reduced the rate of infection from 33% to 7%.

While many hospitals are leveraging these strategies to minimize infections, not all are, notes Nickles Fader.

“Patients should speak to their surgeons about what will be done to mitigate perioperative risk,” she says. “If there is no clear plan, patients may wish to seek a second opinion.”

Of note, patients are advised to seek care from centers that routinely perform large numbers of procedures with a team of physicians and staff that specialize in gynecological or abdominal surgery and also provides adequate explanation and education.

Uncontrolled diabetes can also compromise the immune system and increase the risk of infection, according to Dr. Marcia Ciccone, a gynecologic oncologist at the Keck School of Medicine of the University of Southern California in Los Angeles.

“I make sure the patient’s blood sugar is under good control pre- and postoperatively,” she says.

If patients are very obese, she places a drain in the subcutaneous fat during surgery because excessive depth and volume of subcutaneous tissue increase the risk of infection.

Nutritional deficiencies are also a risk factor for poor wound healing, according to Ciccone.

“A lot of our cancer patients have diminished appetites or nausea, and they have increased metabolic demands due to the cancer,” she says. “Good nutrition and a balanced diet help the immune system, and patients who cannot eat should receive artificial nutrition and hydration after surgery.”

Researchers are also experimenting with electronic systems that give patients an opportunity to report their symptoms in the days following discharge from the hospital. 

Zivanovic recently led a pilot study in which patients recovering from minimally invasive gynecologic surgery answered questions daily to track eight symptoms: pain, nausea, vomiting, shortness of breath, fever, swelling, discharge and redness around the incision. Pain, nausea and swelling were the most commonly reported symptoms.

“If a patient still has moderate to severe pain three to five days after this type of surgery, something may be wrong,” notes Zivanovic.

In these cases, an email alert was sent to the medical team and the patient was told to call the doctor’s office immediately. Most of the participants in the study agreed or strongly agreed that electronic symptom tracking was helpful and easy to use and they would recommend it to others.

Investigators at Memorial Sloan Kettering Cancer Center are also developing a similar tool for patients who are in the hospital for more than three days after complex surgeries.

This type of tool could be beneficial for some patients like Andrea Brockway, 57, of Crestline, California, who received a diagnosis of uterine cancer in 2020
after she started spotting. 

The radical hysterectomy went smoothly, but a week later she noticed that the 5-inch abdominal incision was turning red, was starting to ooze and felt painful. She notified her doctor and the medical team confirmed that the wound was infected.

Her surgeon reopened the incision, drained the infection, prescribed antibiotics and gave Brockway a wound vacuum device that held the edges of the wound together and removed fluid from the area while she was recovering at home.

“Fortunately, my doctor had prepared me as far as what to look for related to signs of infection,” says Brockway. “When I called to report the symptoms, they told me to come in right away.”

The infection healed after two weeks, and she later underwent radiation therapy.

Although studies are exploring strategies to prevent infections like the ones Brockway and Tellez experienced, Dr. Haider Mahdi, a gynecologic oncologist at UPMC Hillman Cancer Center at Magee-Womens Hospital in Pittsburgh, was curious about the level of risk associated with different types of gynecologic surgery.

He and colleagues studied more than 6,800 patients who were diagnosed with SSIs after procedures to treat endometrial, cervical or ovarian cancers. The study authors found that the risk of infection after a laparotomy was 3.5 times higher compared with minimally invasive surgery (7% versus 2%). In the laparotomy group, predictors of SSI included an endometrial cancer diagnosis, obesity, preoperative anemia, ascites (fluid in the abdomen) and perioperative blood transfusion. Patients who developed SSIs were five times as likely to need an additional operation to treat the infection.

“I am using these findings to counsel patients about their level of risk,” Mahdi says. “If someone is obese, for example, I will likely consider whether a minimally invasive procedure is possible, especially in endometrial cancer.”

While the risk of infection is lower with laparoscopy, new research suggests that it may no longer be the preferred option to treat early-stage cervical cancer. 

In a recent study, patients undergoing laparoscopic radical hysterectomy for cervical cancer were more likely to develop recurrences and peritoneal carcinomatosis (a rare cancer of the peritoneum, or the thin layer of tissue that covers most of the abdominal organs) than patients undergoing open surgery.

Danielle Glick, 38, was a candidate for minimally invasive robotic surgery after she received a diagnosis of cervical cancer in 2020, when she also learned that infections may occur months after a procedure.

Her cancer journey began when she started feeling pressure in her lower abdomen and hip. Her Pap smear results came back abnormal, and she underwent a colposcopy (a procedure in which a provider closely examines the cervix, vagina and vulva for signs of disease). 

The biopsy findings showed that she had cancer in her cervix and a portion of her uterus.

Glick, who lives in Connecticut, opted to
have a radical trachelectomy to preserve her ovaries and most of her uterus in case she wanted to have children. During the three months following the robotic surgery, she experienced cramps, abdominal swelling and recurrent urinary tract infections.

She returned to the operating room for a dilation and curettage procedure to remove scar tissue, but in the following months she developed severe abdominal cramping.

“I was so tired of going to the doctor and the hospital, but everything between my pelvic bones felt like it was being crushed,” she says. “I could not find relief, and I became suicidal.”

Glick was diagnosed with an infection known as pelvic inflammatory disease and was started on a 14-day regimen of antibiotics. The medication cured the infection and her pain subsided, but the complications were traumatic emotionally and physically.

She now encourages others not to remain silent and to immediately express what they’re experiencing.

“I wish I had contacted my doctor earlier, but I was afraid that the pain was a sign that the cancer was back,” she says. “It’s important to be aware of the signs of an infection and speak up as soon as the symptoms begin.”

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Articles

The use of newer tools and techniques may be reducing the risk of surgical site infections and other complications in patients receiving treatment for gynecologic cancers.

Uncovering New Ways to Make Cancer Surgery Safer

Krista Bridgmon was 2 years old when her grandfather noticed that the right side of her jaw was enlarged, a symptom marking the beginning of a two-year battle to overcome a cancer of the nerve cells that had spread throughout her body.

Bridgmon, now 30, underwent chemotherapy, radiation, surgery and a bone marrow transplant to treat high-risk neuroblastoma (a cancer that starts during very early formation of nerve cells, mostly occurring in infants and young children), but the cisplatin chemotherapy that helped save her life was ototoxic, or damaging to her hearing.

She struggled to hear high-frequency sounds such as “s,” “th” and “f.” Discerning voices in noisy environments was particularly difficult. She was fitted with hearing aids, but the large, uncomfortable devices were painful and amplified all sounds. Whispering students and shuffling footsteps were sometimes louder than the teacher’s voice. She avoided crowds because it was almost impossible to follow conversations in a group, and she became increasingly shy as time went on.

“I felt embarrassed and less confident,” says Bridgmon, of Arley, Alabama. “I would nod and say, ‘yes’ even when I didn’t know what people were saying.”

She learned to read lips to compensate, but this strategy did not always work. She still relies on hearing aids when helping her daughter with homework or meeting with her doctors.

 after cancer treatment. Ototoxic platinum-based chemotherapy is commonly used to treat certain childhood cancers, including tumors affecting the brain, nervous system, liver and bones.

Krista Bridgmon cannot afford new hearing aids because Medicaid stopped covering this expense once she turned 21.

However, these drugs can cause hearing loss, tinnitus (ringing in the ear) and balance problems. Researchers have found that the platinum accumulates in a part of the cochlea called the stria vascularis, which regulates the makeup of the fluid that bathes sensory hair cells in the ear. The platinum is eliminated from other organs within days or months after an infusion but can be found in the inner ear years after treatment.

, demonstrated that hearing loss is most common among patients younger than 5 when receiving cisplatin, with 60% in this age group experiencing hearing problems years after treatment. Investigators from Children’s Hospital Los Angeles in California analyzed data from more than 1,400 patients in the United States who received cisplatin sometime between birth and age 40.

Investigators found that higher daily and cycle doses of the drug — such as regimens used to treat liver cancer, neuroblastoma and central nervous system tumors — increased the risk of hearing loss. Another study suggests that cranial radiation therapy can also be ototoxic, with 14% of patients reporting hearing loss at least nine years after treatment, according to a study of pediatric patients from St. Jude Children’s Research Hospital in Memphis, Tennessee.

Although studies like these are drawing attention to hearing loss and tinnitus among cancer survivors, there are still significant gaps in understanding how to prevent these long-term side effects, or late effects, and how to help patients experiencing them, says Dr. Emily Tonorezos, director of the Office of Cancer Survivorship at the National Cancer Institute in Rockville, Maryland.

“Hearing loss among cancer survivors has been overlooked and understudied,” she says. “People do not consider it a serious medical problem, and as a result there are many cancer survivors who struggle to communicate, feel isolated and experience neurocognitive difficulties.”

Like Tonorezos, Johnnie Bass, a research audiologist at St. Jude Children’s Research Hospital, suspected that hearing loss was affecting cancer survivors more than most clinicians realized. Parents would share that their children were struggling in school, needed speech and language services and were having behavioral issues.

To explore whether hearing loss was linked to neuro-cognitive function, Bass studied more than 1,500 patients in the St. Jude Lifetime Cohort who had survived childhood cancer five years or longer. Hearing loss in this population was associated with deficits in attention, executive function, processing speed, intelligence and academic function.

“The hearing loss can begin within days or weeks after treatment, and the damage is permanent,” Bass explains. “And the hearing problems can worsen over the years as people age.”

Hearing loss affects not only cognitive function among childhood cancer survivors, but also social development. Tonorezos recently interviewed childhood and young adult cancers survivors who were exposed to cranial radiotherapy, platinum chemotherapy or both, and hearing loss was associated with isolation and feelings of exclusion. Many of the survivors had deprioritized or neglected their hearing issues because the problem was a reminder of their cancer history, and they did not want to spend time and energy on hearing loss testing or treatment, says Tonorezos.

As awareness increases about the prevalence of treatment-induced hearing loss, researchers hope providers will not only prioritize early screening to identify who may be at risk, but also refer patients to specialists who can provide treatment. Before starting potentially ototoxic therapies, clinicians should explain the potential immediate and long-term effects on the inner ear, says Kathleen Castro, a nurse consultant in the Office of the Associate Director of the Healthcare Delivery Research Program at the National Cancer Institute in Rockville, Maryland.

“If an ototoxic therapy is the best treatment for the cancer, in most cases the decision to move forward is clear,” she says.

But it is optimal for these patients to receive a baseline audiology test before starting treatment. Subsequent hearing tests can be compared with this baseline, says Castro.

“It is so easy to get focused on the moment when facing cancer, but it’s also critical to weigh what is at risk with long-term survival,” she says. If patients begin to show signs of hearing impairment, reducing the dose of chemotherapy may be a way to decrease risk of further damage, she adds.

To standardize audiology care for pediatric patients receiving ototoxic therapy, a group of international experts gathered to develop guidelines for clinicians. They determined that monitoring hearing and counseling from an audiologist should be considered before each ototoxic chemotherapy cycle. The specific monitoring recommendations for each patient are based on context, including the diagnosis, the drug, the dose and the child’s age.

The investigators found compelling data suggesting that, after treatment has been completed, “the screening needs to be tailored to a child’s age,” says Wendy Landier, one of the study authors. “Very young children should be screened more frequently than older children, but everyone who receives ototoxic therapy needs to be screened even as they move into adulthood,” explains Landier, deputy director of the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham. Children under 6, for example, should be screened for hearing loss every year, and those from 6 to 12 should be screened every two years. For those 13 and older, screening is recommended every five years, according to the study.

If hearing loss is detected, clinicians can refer patients to an audiologist.

“These specialists are underutilized, and they are very knowledgeable about the resources available to address hearing loss,” Landier adds.

Raeanna Butcher, 33, of Montclair, New Jersey, benefited from seeing an audiologist but waited several years after cancer treatment because she was skeptical that hearing aids would help. She was diagnosed with pediatric osteosarcoma (a tumor that almost always occur in the bone, commonly near the growth plates of the knee, arms, legs and pelvis) during her sophomore year of college after her left knee started hurting during volleyball practices. She received two rounds of cisplatin before undergoing surgery to remove the cancer in her knee, and audiogram results during treatment revealed that she was suffering from high-frequency hearing loss.

During the two years after treatment, these issues resolved but Raeanna Butcher noticed the hearing loss was persistent. She would frequently ask people to repeat things and felt self-conscious in loud social settings when it was hard to hear.

But this problem was overshadowed by more acute consequences of treatment, including six months in a straight leg cast, mouth sores, numbness and tingling in her feet and complications from an intestinal bacterial infection.

During the two years after treatment, these issues resolved but Butcher noticed the hearing loss was persistent. She would frequently ask people to repeat things and felt self-conscious in loud social settings when it was hard to hear.

“I knew I was fortunate to have survived and wanted to put cancer behind me, but the hearing loss was always with me,” she says.

Butcher finally decided to see an audiologist, who explained that hearing aid technology had improved significantly over the years. He gave her a device programmed to help her hear high-frequency sounds, and for the first time in years she could easily follow conversations at large business events and social gatherings, including her own wedding.

Health insurance coverage for hearing aids for children and adolescents varies by state, and only a few states require insurance companies to cover hearing aids for adults, says Landier.

“Cost is a big problem,” says Bass, who found that only 23% of the cancer survivors with severe hearing loss in her study were using a hearing aid or cochlear implant.

Butcher paid $5,000 for her hearing aids; Bridgmon cannot afford new ones because Medicaid stopped covering this expense once she turned 21.

Researchers are starting to explore the possibility of preventing ototoxicity by using drugs such as sodium thiosulfate (STS), an antioxidant that binds to harmful molecules produced in cells that have taken up cisplatin. Scientists are working to understand why STS is otoprotective; they suspect the drug prevents free radicals from damaging the hair cells in the inner ear. It is also possible that STS binds to platinum, which could prevent residual cisplatin from killing cells in the ear.

, children with localized liver cancer received STS six hours after each infusion of cisplatin. They were half as likely to experience permanent hearing loss as children who did not receive STS, and the drug did not decrease the effectiveness of the chemotherapy.

For now, STS is not widely used in cancer institutions, in part because more research is needed to determine whether the drug impacts the effectiveness of chemotherapy, says Dr. Stefanie Thomas, director of adolescent and young adult oncology at Cleveland Clinic Children’s in Ohio.

“For now, clinicians are sometimes using STS in children diagnosed with localized cancer, but not yet in metastatic disease,” she explains.

In the future, providers may also be able to identify genetic risk factors for ototoxicity. Childhood cancer survivors from the St. Jude Lifetime Cohort who underwent cranial radiation therapy were more likely to have hearing loss and tinnitus if they had a specific gene variation in certain chromosomes, according to a recent study.

 how cisplatin affects hearing and tinnitus in survivors of adult-onset cancer. Eager to study this patient population, Robert Frisina, director of the Global Center for Hearing & Speech Research at the University of South Florida, joined a multi-institutional team that is following more than 2,000 testicular cancer survivors who received platinum-based therapy. They found that 20% had hearing loss classified as severe to profound and 40% had tinnitus.

These initial findings were based on audiogram testing in which participants pressed a button if they heard a specific tone. The team now plans to expand the testing to evaluate speech processing amid background noise.

“I think our findings may surprise some oncologists,” says Frisina. “They may not realize that the hearing loss is so severe.”

He hopes that his work will highlight the consequences of ototoxic treatment, and ultimately help providers to be more attentive to cancer survivors who need audiological support and hearing aids.

Although awareness of this issue is increasing, screening and access to audiologists are not widespread. In the meantime, cancer survivors like Butcher encourage patients to be proactive in addressing hearing loss and tinnitus.

“Don’t continue to suffer,” she says. “I tried to ignore the problem because I didn’t want the effects of cancer to be part of my life, but it’s wise to educate yourself, talk to an audiologist and see what is available.”

Significant challenges include improving detection and response to inner ear side effects among cancer survivors following the use of certain drugs and therapies.

Listen Up: Hearing Loss Among Cancer Survivors Often Overlooked and Understudied

For patients who have undergone surgery to remove colon cancer, one of the significant stressors is waiting to see if CT scans show that the cancer has recurred.

Now, new technology to detect cancer much earlier may alleviate the agonizing wait and lead to better outcomes. In 2020, Medicare recommended coverage for a new test that detects small amounts of circulating tumor DNA (ctDNA) in the blood of patients who previously received a diagnosis of certain types of cancer.

The Signatera test, developed by Natera, is being used in a clinical trial looking at how well the ctDNA testing works to predict the benefit of chemotherapy treatment after surgery for stage 3 colon cancer.

® spoke with Dr. Scott Kopetz, a professor in the department of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center in Houston, about the test’s potential value for patients.

“In early stage 2 colon cancer, for example, we do not typically recommend chemotherapy, but what if the test came back positive for cancer in the blood?” he said. “Then we might suggest chemotherapy.”

In patients with stage 3 disease, chemotherapy is usually prescribed, but a negative ctDNA test result might indicate that this treatment is not needed, Kopetz explains. The new blood test detects unique mutations in a patient’s tumor and has been shown in clinical studies to identify residual disease up to two years earlier than standard imaging.

“The challenge now is learning what to do with the information we gather from the test, but ultimately I think this technology will dramatically accelerate our ability to cure more patients,” Kopetz says.

To read more on how the identification of rare genomic alterations in patients with colorectal cancer has given oncologists the opportunity to treat patients who otherwise might not have many options, 

®’s recent special gastrointestinal cancers issue.

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A new technology that can detect small amounts of circulating tumor DNA in the blood of patients who previously received a diagnosis of certain types of cancer may dramatically accelerate the ability to cure more patients, says an expert from the University of Texas MD Anderson Cancer Center.

A New Frontier: Identifying Traces of Colorectal Cancer in the Blood

When Mia Balko, 48, started experiencing an ongoing cough in early 2019, her primary care doctor treated her with medication for acid reflux disease, but the cough persisted. Then she noticed that her abdomen was becoming increasingly distended and firm, and she asked to see a gastroenterologist.

Balko, who lives in Waco, Texas, was shocked when she later learned that the cough had been triggered by stage 4 colon cancer. The disease had spread to her abdomen and caused fluid retention, which in turn pressed on her lungs. Balko initially received two different chemotherapy regimens over the course of a year, but despite each treatment, the disease continued to grow.

The cancer tested positive for a specific gene mutation known as KRAS G12C, which made Balko eligible to participate in a clinical trial at The University of Texas MD Anderson Cancer Center in Houston for a new targeted therapy known as AMG 510 (sotorasib). She started taking eight pills daily that contained a small molecule equipped to bind to a region of the KRAS G12C protein. Initially the only side effect was headaches, but once she started taking the medication before bed, the headaches disappeared. After nearly a year on the new targeted treatment, her scans showed that the cancer was stable.

“My quality of life improved when I switched to the targeted therapy,” Balko says. “I had a lot more stamina to work and do activities I enjoy.”

Although a recent scan showed a new lesion on her liver, she is grateful she can continue taking AMG 510 as she adds a new chemotherapy treatment to her regimen to address the growth.

For years, the only main targeted therapy available to patients with colorectal cancer was a medication that blocked the function of a protein called epidermal growth factor receptor (EGFR), but this treatment was not effective for patients with the KRAS mutation, which is present in approximately 40% of colorectal cancers. Now researchers are uncovering new treatments that are improving outcomes for people with colorectal cancer who have this mutation and other genetic aberrations, including the BRAF mutation and HER2 amplification.

“Compared (with) other forms of cancer, results of targeted therapy agents have not been as impressive in colorectal cancer, but we have learned from many negative trials,” explains Dr. Afsaneh Barzi, a gastrointestinal medical oncologist at City of Hope Comprehensive Cancer Center in Duarte, California. “With the new clinical trials, we are right on the cusp of seeing significant changes in outcomes for this population of patients.”

Colorectal cancer is the third-leading cause of cancer deaths in the United States, and Barzi notes it is critical for patients to receive molecular testing at diagnosis to identify potential genetic targets. “Sometimes doctors wait to do this testing until patients have failed on standard therapy, but this is too late,” she says. “We need this information early on to identify potential clinical trials.”

For patients who do not have the KRAS mutation, which is known as KRAS wild-type, EGFR inhibitors combined with chemotherapy can slow progression of the disease, but more recent studies have shown that there is one more element to consider for these patients: the cancer’s location.

“When scientists analyzed the study results, they discovered that EGFR inhibition with first-line chemotherapy only worked with people who had left-sided colon cancers,” says Dr. Alfred Neugut, co-director of the Cancer Prevention Center at New York Presbyterian Hospital and Columbia University Medical Center’s Herbert Irving Comprehensive Cancer Center. For right-sided tumors, the better option for first-line treatment is chemotherapy plus Avastin (bevacizumab).

New Strategies for Treating BRAF and HER2 Cancers

The BRAF mutation — which occurs in approximately 10% of colorectal cancers — is another biomarker that has historically been difficult to target in patients with colorectal cancer, but researchers have started to uncover new ways to improve outcomes for this population.

“More than a decade ago, we recognized that this group of patients was not responding to traditional therapies, so initially we tried targeting the BRAF mutation,” notes Dr. Scott Kopetz, a professor in the department of gastrointestinal medical oncology at MD Anderson. “This strategy had worked in patients with melanoma, but we found that this was not the case for people with colorectal cancer.”

Researchers discovered that when they used a drug to block a receptor on BRAF-mutated cells, the cells increased EGFR signaling to compensate and continue cancer growth. Then Kopetz launched clinical trials in which patients received either one or two BRAF inhibitors in addition to an EGFR inhibitor, and this was more successful. In April 2020, the Food and Drug Administration (FDA) approved Braftovi (encorafenib), a BRAF inhibitor, in combination with Erbitux (cetuximab), an EGFR inhibitor, for patients with metastatic colon cancer. Findings from the recent BEACON CRC study showed that these combinations increased overall survival by more than four months. The most common side effects included diarrhea, acne and nausea.

Now researchers are exploring benefits of adding chemotherapy to this regimen or combining BRAF inhibitors with immunotherapy. Mary DeForest, 59, recently enrolled in a clinical trial for a combination of Braftovi and Erbitux plus the immunotherapy drug Opdivo (nivolumab) to treat stage 4 colon cancer, and she has been impressed by the results. After four months on the combination, the tumor in her liver has shrunk 75% and the cancer in her colon decreased 25%. “I feel so good that I don’t think about having cancer anymore,” DeForest, from Bay City, Texas, says.

Another promising target in colorectal cancer is the HER2 amplification, which means the cancer has too many copies of the HER2 gene. The amplification occurs in approximately 3% to 5% of colorectal cancers, and clinical trials combining two HER2-targeted therapies have shown that this strategy can have impressive results, according to Dr. James Cleary, a senior physician at Dana-Farber Cancer Institute in Boston.

One of Cleary’s patients has been taking a combination of Herceptin (trastuzumab) and Tykerb (lapatinib) for four years with an excellent quality of life, and now there is a second option for her if the cancer starts to grow.

Enhertu (trastuzumab deruxtecan) is an antibody-drug conjugate that binds to cells with the HER2 amplification and then delivers a toxin into these cancer cells. Results of a recent study showed that, among patients with the highest levels of HER2 expression, the response rate to this drug was 45% and the median progression-free survival (the time from treatment to disease progression or worsening) was seven months.

Genomic testing of cancer cells can reveal not only the presence of KRAS, BRAF and HER2 alterations but also the level of microsatellite instability (MSI). People who are MSI-high are deficient in the mismatch repair (MMR) proteins that find mistakes in DNA. These MSI high cancers accumulate DNA mutations that are felt to make tumors more recognizable, which is good news now that immunotherapy is an option for treatment.

“Immunotherapy uses the body’s own immune system to fight off cancers, and tumors with more mutations are easier to identify as invaders,” Cleary says. “The challenge is that only about 3% to 4% of people with metastatic colon cancer are MSI-high, so not many patients can benefit from immunotherapy at this point.”

Rodnell Workman, 47, was among the patients with stage 4 colon cancer who were eligible for immunotherapy. His symptoms began in 2016, when he felt as though he had the flu and later discovered that his appendix had ruptured. The surgical team identified abnormalities on his appendix and a colonoscopy showed that he had a large mass in his colon. Biomarker testing revealed that he had Lynch syndrome, an inherited condition associated with high levels of MSI and increased cancer risk. The doctors prescribed chemotherapy to shrink the tumor before removing it surgically, and they also recommended three months of the immunotherapy Keytruda (pembrolizumab) to ensure that the cancer was eradicated.

“I had no side effects from the immunotherapy and I’ve had clean scans ever since,” says Workman, who lives in New Jersey.

Although Workman received immunotherapy after chemotherapy, in June 2020 the FDA approved Keytruda as a first-line treatment for patients with colorectal cancer that is MSI-high, MMR deficient or unresectable. Researchers also have started to investigate whether immunotherapy in combination with Stivarga (regorafenib), which inhibits growth of blood vessels needed for tumor growth, could benefit the many patients with tumors that are not MSI-high.

Although oncologists have more targeted therapy options for patients with colorectal cancer than in the past, the treatments are still limited to a somewhat small percentage of patients who have certain mutations, says Dr. Suneel Kamath, a medical oncologist who specializes in the treatment of gastrointestinal cancers at Cleveland Clinic in Ohio. “The biggest area of need is finding more mutations and developing drugs to target them,” he says.

For example, fibroblast growth factor receptor (FGFR) mutations in bile duct and bladder cancer have also been found in colon cancer. Clinical trials are underway to test whether Pemazyre (pemigatinib), an FGFR inhibitor that targets this mutation, blocks tumor growth in people with metastatic colon cancer.

Moreover, mutations in the RAS gene family have been known to be bad actors for decades — associated with more aggressive behavior in many tumor types — and were considered “undruggable” until recently.

Cleary said he hopes to see more studies that explore repurposing targeted treatments for other forms of cancer to help people with colorectal cancer. As part of one study, Cleary and his Dana-Farber colleague Dr. Harsh Singh treated two patients with colon cancer who tested positive for gene translocations seen in lung cancer: ROS1 and ALK. They prescribed targeted therapies that have been effective in lung cancer, and the results were encouraging. The treatment was beneficial for seven months for the patient with the ALK translocation, and the patient with the ROS1 translocation continues to do well after more than a year of targeted treatment.

“To me, this was very exciting,” Cleary says. “Seeing (patients with colorectal cancer) with these rare genomic alterations benefit from nontraditional therapies gives me hope that additional targetable alterations can be found and exploited, and, hopefully, this is just the beginning.”

The identification of rare genomic alterations in patients with colorectal cancer gives oncologists the opportunity to treat patients who otherwise might not have many options.

Heather Stringer

Uncovering New Ways to Make Cancer Surgery Safer

Listen Up: Hearing Loss Among Cancer Survivors Often Overlooked and Understudied

A New Frontier: Identifying Traces of Colorectal Cancer in the Blood

Overcoming Obstacles to Targeted Therapy in Colon Cancer

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