Organ-Sparing Treatments Bring New Life After Cancer

When Sarah Rack talks about her diagnosis of rectal adenocarcinoma on Election Day 2020, she does not mince words.

"I was suicidal," she says firmly.

It was the fear of illness and death, concern for her children — one a college sophomore at the time and the other still in high school — and the threat of surgical removal of her rectum and living the rest of her life with a colostomy, the surgical connection of the colon to an abdominal opening that lets stool be collected in a bag outside the body.

"Now, I'd be able to handle it better, but at the time, I said I'd rather be dead than have a colostomy. I was so depressed," says the 58-year-old psychiatrist who lives in Memphis, Tennessee.

But Rack was offered a possible escape from that fate: a spot in a clinical trial that would test whether treatment with medication alone could eliminate the need for surgery in people with tumors that had specific genes that suggested they would respond well to the medication.

Surgical removal of the affected organ was once a foregone conclusion in many cancers, including certain cancers of the rectum, colon, stomach, bladder and uterus. These life-altering surgeries may have consequences for digestion, excretion, fertility, sexual function and countless other aspects of daily life. But now, an increasing number of people with some of these cancers have a choice: surgical removal of the organ or systemic therapy and added surveillance.

“Depending on the organs involved and what the surgical pathway would have looked like, surgical resection can greatly reduce your quality of life,” says Dr. Kaysia Ludford, an assistant professor in the Department of General Oncology at The University of Texas MD Anderson Cancer Center in Houston. “An organ-sparing approach is paradigm-shifting.” 

Life-Altering Surgery

Although the removal of an organ often offers the greatest chance of a cure in cancers such as rectal and bladder, these surgeries come at a cost. For some people, rectal resection can mean living with a permanent colostomy along with other potential collateral effects. “Even with a minimally invasive approach, we can affect sexual function, bladder function and fertility,” says Dr. Fergal Fleming, a colorectal surgeon at the University of Rochester Medical Center in New York.

The same is true of bladder removal, a procedure called radical cystectomy, for bladder cancer. The procedure not only takes the bladder but also part of the small intestine, which is used to create a “neobladder,” a pouch to hold urine. Nearby organs and tissue are also removed, which can affect fertility and sexual function.

"It’s fraught with complications," says Dr. Roger Li, a genitourinary oncologist at Moffitt Cancer Center in Tampa, Florida, "because it’s one of the most complex surgeries we do in urology, and it’s oftentimes done in a patient population who is not at their healthiest."

Saving Organs in Cancers With Specific Genes

Rack got into a clinical trial at MD Anderson that tested whether treatment with the immune checkpoint inhibitor Keytruda (pembrolizumab) before surgery might eliminate the need for surgery in people whose tumors had cells with mutations in genes that correct DNA errors, a condition known as mismatch repair deficiency.

Twenty-seven of the 35 trial participants, including Rack, had colon or rectal adenocarcinoma. The remaining eight had adenocarcinoma of the stomach, pancreas, duodenum (an upper part of the small intestine), ampulla (a small opening that enters the duodenum) or uterus. One patient had a type of brain tumor called a meningioma.

They received Keytruda every three weeks for six months. At the six-month mark, they could have surgery or continue the medication for a year, followed by observation.

Eighteen participants chose the nonsurgical option of Keytruda, 10 of whom completed the full year. After three years of follow-up, 14 of the 18 patients were alive with an intact organ. Two patients were lost to follow-up. One patient died of unrelated causes. Another died from disease progression. Although the majority of those in the study and the majority who benefitted from treatment had colorectal cancer, one patient who took the nonsurgical option had gastric cancer and is still in remission now, nearly four years later.

“The patient still has the organ intact and didn’t require the stomach to be resected,” says Ludford, who co-led the study. “As you can imagine, certain organs have serious implications for quality of life if they have to be resected, [such as] the stomach, for instance, so we want to explore the possibility of sparing those organs, and that’s what led to this study.”

The results were published in 2023 in the Journal of Clinical Oncology. In a similar study, 14 people with locally advanced rectal cancer with mismatch repair deficiency had a complete clinical response to the immunotherapy drug Jemperli (dostarlimab), which works in the same way as Keytruda, eliminating the need for surgery.

Total Neoadjuvant Therapy

Rectal tumors do not have to carry the mismatch repair deficiency mutation to be eligible for a nonsurgical approach. The treatment plan for many rectal cancers used to be what is called “sandwich therapy,” Fleming says. “You got a little bit of radiation and a very small dose of chemo, which we call a sensitizing dose; then you’d have surgery and then three to six months of chemo afterwards.” But now researchers are testing the effects of front-loading the treatment plan with all the systemic therapies and radiation and then reassessing to see whether the patient still needs surgery.

Not too long ago, Fleming says, “Chemoradiation [for rectal cancer] without surgery would have been considered heresy.” Now, he adds: “Sometimes very well-read, motivated patients say they don’t want surgery, and also, we started seeing very good responses to systemic therapy. It wasn’t actually the primary end point of some of these studies, but they started realizing patients had a complete response.”

The approach is showing promise in many other cancers as well. Published research has explored the effects of organ-sparing approaches in cancers of the throat, vagina, sinus cavity and bladder.

Facing the Choice

Organ-sparing treatment for bladder cancer has allowed 65-year-old Darrell Murray of Orlando, Florida, to keep his bladder intact since his cancer diagnosis in 2016 and, for the most part, carry on with life as usual.

Murray had non-muscle invasive bladder cancer, an early-stage cancer restricted to the lining of the bladder. He got the standard therapy — 21 rounds of bacillus Calmette-Guerin (BCG), a combination therapy that includes a cancer vaccine and immunotherapy. Afterward, he was cancer-free until a recurrence in 2020.

The thinking in bladder cancer has typically been that if it recurs after BCG, there is a higher risk for it to spread into the muscle wall of the bladder, becoming what is called muscle invasive and eventually metastasizing. “There has traditionally been this aggressive approach that once you develop recurrence, it’s an indication for us to perform radical cystectomy to remove the bladder and reconstruct the urinary tract,” Li says.

Since 2020, Murray has had four recurrences. “Every physician, every time,” Murray says, “would bring up cystectomy as an option. I realize that’s the gold standard, but I had to ask myself what life would look like with a cystectomy.”

It did not look very good to him.

“They would take the bladder, prostate, lymph nodes and about 18 inches of your intestine to create a vessel for urine,” Murray says. “But the intestines are designed to absorb nutrients, not store urine. You’d absorb waste products from your kidney in the neobladder. There’s mucus buildup and sometimes blockages, so you have to catheterize yourself.”

Increasingly, people like Murray with recurrences of non-muscle invasive bladder cancer are being offered alternatives to surgery. At every turn, Murray has chosen to keep his bladder and receive the next available medication. He reasons that even after radical cystectomy, there is no guarantee a recurrence will not happen.

After Murray’s first recurrence, he had six rounds of Keytruda; after another recurrence, he had eight rounds of chemotherapy; on the third recurrence, he had BCG plus interferon, which helps the body’s immune system fight diseases.

Finally, at the fourth recurrence, Murray was almost ready to give in and have his bladder removed when he was offered a spot in the BOND-003 trial led by Li at Moffitt Cancer Center. In this trial, people with non-muscle invasive cancer that did not respond to BCG received 21 treatments with the oncolytic, or tumor-destroying, virus cretostimogene grenadenorepvec (CG0070), designed to replicate inside cancer cells and kill them. It also releases a protein that helps the immune system kill cancer cells.

Murray was among the more than 75% of trial participants who had a complete response to the treatment. The Food and Drug Administration has granted the experimental drug both fast-track and breakthrough therapy designations to speed its path to approval. Research is underway to test the same approach in muscle invasive bladder cancer.

Murray is once again cancer-free. He has been for over two years.

Although he has no regrets about keeping his bladder intact, the treatments he has endured over the past eight years have been no picnic, he says. Bladder cancer medications are intravesical, which means they go directly into the bladder, and the patient must hold them in, resisting an intense urge to urinate, for a half-hour or more. “I kind of liken it to battery acid, Coca-Cola and a package of Mentos,” Murray says of the sensation. “It was really tough sometimes.” The more treatments he underwent, the harder it was.

Is Organ-Sparing Treatment Right for You?

Each time Murray faced a recurrence, he carefully weighed the surgical versus nonsurgical approach. “I wouldn’t say it was a no-brainer,” he says.

People who have the option of organ-sparing cancer treatment should consider several issues. First, they should understand their individual risk of recurrence and whether a recurrence might be more aggressive.

They should compare the options. When comparing the removal of a vital organ and treatment with medication, organ removal typically requires a longer recovery and significant adjustment to a new life without the organ. Still, those facing this choice should ensure that they can tolerate the intense medication therapy they would receive instead of organ removal. That includes possible side effects from medication and downtime after treatment days.

Patients should also understand what kind of follow-up will be needed in the coming months and years. A nonsurgical approach usually requires more follow-up, imaging and testing than would be required of someone who had the organ removed. This is to ensure the cancer has not come back and to catch it early if it has.

The treatment and intense follow-up often require travel to a large cancer center. “Individuals need to have access to the medical facility where they can continue this very close monitoring,” Ludford said. Transportation, additional time, added costs, time away from work and child care or eldercare may all figure into this increased monitoring.

Finally, organ-sparing treatment might be best suited to people who are less prone to anxiety. All those follow-up tests can be a source of great anxiety.

“This is something we chat with our patients about,” Fleming says. “How do you cope with uncertainty? Some people can just shut the door on uncertainty while others just can’t stop looking at the issue.” Most patients in Fleming’s practice who choose to watch and wait, even if they have a recurrence, are happy with their decision, he says.

Rack, the psychiatrist in Memphis who had rectal cancer, traveled to MD Anderson in Houston for Keytruda infusions every three weeks for 18 months. After finishing treatment, she went back to Houston for scans and labs every three months for about a year. Now, she goes every six months.

Today, cancer-free, she says she actually enjoyed the trips to the cancer center in Texas. “The treatment down there was great, and then I’d come back to work and put it out of mind,” she says.

As for whether Rack regrets holding onto the organ where her cancer scare began, there is no question she made the right choice, she says. “This is one of the happiest times in all my life.”

For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.