Human Touch Surgeries, New Therapies Brighten the Picture in Endometrial Cancer

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From Turning Point 2017
by Robert Levy

Although she had been fully prepped on what to expect, Barbara Losordo was a bit surprised at the ease and speed of her recovery from surgery for endometrial cancer. Discharged from the hospital the same day she had undergone the procedure, she needed no pain medication afterward. Within a week, she was driving. Within a month, she was back in the gym.

"I felt so good it didn’t seem like a major operation," says the mother of two adult children, who lives with her husband on Cape Cod. Her experience exemplifies how an approach to endometrial cancer, championed at the Susan F. Smith Center for Women’s Cancers at Dana-Farber, is helping women make a full return to their lives.

The approach includes reducing the impact of hysterectomy, the standard treatment for endometrial cancer, so patients can recover more quickly with fewer complications and shorter hospital stays. In one area, in particular, surgeons at Brigham and Women’s Hospital (BWH), Dana-Farber’s partner in adult care, are demonstrating that human skill can outperform robot-assisted surgery in some patients.

Endometrial cancer, which arises in the lining of the uterus, is the most common form of gynecologic cancer. This year, an estimated 61,000 women in the United States will be diagnosed with the disease. Often detected early, it can usually be cured by surgery and, if necessary, a combination of chemotherapy, radiation, and hormonal therapy.

While research is under way to improve cure rates even further, "the treatment of the disease is itself turning a corner, with a growing use of minimally invasive, laparoscopic procedures, says Losordo’s surgeon, Colleen Feltmate, MD, director of minimally invasive surgery in Gynecologic Oncology at BWH.

Laparoscopic surgery uses a small camera and long instruments inserted through small incisions. Doctors began using laparoscopic surgery for hysterectomies and biopsies to detect cancer spread in the 1990s. It was an improvement over open surgery, which required large incisions and increased the chance of infections and other complications.

Around 10 years ago, hospitals around the country began acquiring technology that allows the surgeon to manipulate these tools via a robotic arm. The robotic technique is especially useful for patients who are obese or have a complicated surgical history with a lot of scar tissue in the pelvis.

Many surgeons, however, find that using conventional laparoscopic technique without robotic assistance allows them to complete the operation in less time, with fewer and smaller incisions, and with equally good results. Fewer surgeons use conventional laparoscopy because it requires more training, but the benefits – shorter operations and lower costs – are hard to argue.

At most hospitals in the United States, robot-aided procedures remain the standard for patients with endometrial cancer. At BWH, by contrast, fully 80-85 percent of such surgeries are performed laparoscopically without robotic assistance.

This approach has had a demonstrable effect on recovery times, Dr. Feltmate says. "Ten years ago, patients were usually in the hospital for three or four days and were out of work for about six weeks. Today, 70-80 percent of our patients go home the same day as surgery. Like Barbara Losordo, many can drive in a week and are often back at work in two to four weeks."

Sparing the Nodes

Another tissue-sparing advance involves checking the lymph nodes around the uterus for cancer. Traditionally, surgeons would remove 15-20 nodes and examine them for cancer cells that may have escaped the uterus. The procedure is critical to identifying patients at risk for metastatic cancer, but the removal of so many nodes can create new problems, particularly lymphedema, a blockage of lymph flow that can cause a painful swelling of the legs and increased susceptibility to infection.

Borrowing a technique from breast cancer and melanoma surgery, gynecologic surgeons at BWH use a more selective procedure known as sentinel lymph node mapping. Before the operation, the surgeon injects a fluorescent dye at two precise locations in the patient’s cervix. Lymphatic channels carry the dye to the sentinel nodes – the first nodes that cancer cells are likely to reach if they leave the uterus.

When the uterus is removed, the sentinel nodes are also removed and immediately examined for tumor cells by a pathologist. Sentinel node removal dramatically reduces the risk of lymphedema and its morbidity as compared with more complete node removal. It usually takes a week for all the biopsies to be complete. Depending on the results of these exams, patients may require additional treatment such as chemotherapy or radiation therapy. The good news is that most patients are cured by surgery alone.

Research and Recommendations

Panos Konstantinopoulos, MD, PhD, is testing checkpoint inhibitors for endometrial cancer.

At Dana-Farber, the approach to endometrial cancer encompasses genetics and prevention as well as a range of research studies.

On the genetic side, Huma Rana, MD, clinical director of the Center for Genetics and Prevention, and her colleagues counsel patients who test positive for Lynch syndrome, a hereditary condition that increases one’s risk of developing endometrial cancer, as well as cancers of the colon, stomach, small intestine, pancreas, liver, or other organs. "By identifying people with Lynch syndrome, who often come to us because of a strong family history of endometrial or colon cancer, we can recommend screening to find these cancers early or offer surgery to reduce chances of developing them," Dr. Rana says.

In addition, scientists at the Susan F. Smith Center are leading several clinical trials of new agents for patients with advanced or otherwise hard-to-treat endometrial cancers. One early-stage trial is testing an immunotherapy drug called avelumab, a "checkpoint inhibitor" that seeks to unleash an immune system attack on tumor cells. The study, initiated and led by Panos Konstantinopoulos, MD, PhD, of the Gynecologic Oncology Program at the Susan F. Smith Center, is the first to test an immunotherapy agent in patients with endometrial cancer.

The trial includes patients whose tumor cells have a flaw in the mismatch repair (MMR) pathway – a genetic system that repairs certain kinds of DNA damage. These mutations can be inherited, as in Lynch syndrome, or occur only in the tumor cells. Research by Dr. Konstantinopoulos and his colleagues suggests that such tumors may be especially susceptible to immune checkpoint inhibitors. "The study is still under way, but early indications are that several patients, including some with MMR pathway abnormalities, have responded well to the drug," he observes.

For uterine serous cancer – an aggressive type for which there few good treatments – investigators plan to test a drug that blocks a key stage of the cell-division cycle. The cycle includes several pauses that allow the cell to “proofread” its DNA and make corrections. Many endometrial cancers barge right through one such pause because of a mutation in the gene TP53. The resulting accumulation of DNA damage, however, is often repaired during a second pause, controlled by the gene wee1.

The clinical trial, to be led by Joyce Liu, MD, director of Gynecologic Oncology Clinical Research in the Susan F. Smith Center, will examine the safety and effectiveness of a compound known as AZD1775, which inhibits wee1. The hope is that by hindering DNA repair in cancer cells already hobbled by a broken TP53 gene, the compound will create such a buildup of DNA damage that the cancer cells can no longer survive. Investigators hope to open the trial in 2017.

Turning Point 2017 Table of Contents

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