An Innovative Approach to Chemotherapy

Erena van der Heijden, 61, of Glendale, California, had been treated extensively for her ovarian cancer. After receiving her diagnosis in 2013, she had a total hysterectomy and received chemotherapy. When the cancer recurred in 2017, she had more surgery, where much of her colon was removed.

But neither surgery nor a wide array of drugs stopped her cancer, in large part because of the type of ovarian cancer she had. Called low-grade serous ovarian cancer, it is a rare cancer characterized by small tumors in the peritoneum, the thin layer of tissue that lines the abdominal cavity and wraps around several organs and tubes that connect them.

This type of cancer is hard to treat because these small tumors are slow growing and don’t have an extensive network of blood vessels, making it difficult for chemotherapy administered through infusion to reach them. What’s more, this type of ovarian cancer is often resistant to chemotherapy. In addition, van der Heijden had developed ascites, a buildup of cancer cell-containing fluid in the abdomen.

Having tried a variety of treatments — including chemotherapy, hormone therapy and targeted therapy — with limited success, van der Heijden turned to her doctors for other options. They referred her to a trial being conducted at City of Hope, in Duarte, California, under the direction of Dr. Thanh Dellinger, principal investigator and a gyne- cologic oncologist and surgeon. Two other sites — Northwell Health in New York and Mayo Clinic in Jacksonville, Florida — are also part of the trial.

The trial is testing PIPAC, or pressurized intraperitoneal aerosolized chemotherapy, which is unique in that the chemotherapy is sprayed directly onto the tumors that lie on the surface of the abdominal cavity. This process is designed to make absorption of chemotherapy by the tumor cells more efficient and hopefully more effective. Using laparoscopic surgery, small incisions are made into the abdomen and an aerosolized form of chemotherapy is spread in the area and left there for about a half an hour.

“We have animal data showing that the pressurized approach goes deeper into the tumor, while the aerosol helps deliver the chemotherapy more widely throughout the abdomen,” says Dellinger. “Although this procedure is given after patients have received three or four lines of treatments and is not designed to be curative, it can provide significant relief.”

That has been van der Heijden’s experience. PIPAC has given her a much-needed reprieve from both the cancer and the unsuccessful treatments she has endured.

“The side effects were so much less than they’ve been for either intravenous chemotherapy or the oral form,” she says. “The biggest problem was fatigue, which could last anywhere from 24 hours to four days. There is also some healing from the incisions. But even with those issues, I’m a big fan of the procedure.”

“Erena has responded so well to the treatment that we gave her six treatments instead of the usual three,” Dellinger adds. “Her markers for ovarian and peritoneal cancers have dropped to levels within the normal range, and the ascites disappeared. It’s very interesting that a chemo-resistant kind of cancer is responding when the chemo is delivered a different way. We’re trying to figure out why that’s the case.”

PIPAC was first developed in Europe, and the technology has been available there for about a decade. In recent years, interest in PIPAC has grown in the United States largely because systemic chemotherapy has not been successful in treating peritoneal tumors. The search for alternative approaches resulted in this multisite clinical trial, the first testing PIPAC in the United States.

“Unlike in Europe, the United States requires approval from the Food and Drug Administration (FDA) before a treatment can become standard of care,” says Dellinger. “This phase 1 clinical trial, which currently has about 25 patients at City of Hope, was designed to determine safety and efficacy, which we have already done.”

Dr. Richard Lawrence Whelan, chief of colorectal surgery at Northwell Health system and the Northwell Health Cancer Institute, is spearheading Northwell’s PIPAC clinical trial as an affiliate site of the PIPAC trial led by City of Hope.

“We’ve done 18 PIPAC treatments on four patients,” Whelan says. “In two of our patients, one with colorectal cancer and the other with appendiceal cancer, the PIPAC decreased the amount of tumor such that they were now eligible for debulking, or removing the tumors on the organs, and applying HIPEC (hyperthermic intraperitoneal chemotherapy), heated chemotherapy spread onto the clean abdominal cavity. Unlike PIPAC, which is a palliative form of treatment, surgical resection and HIPEC have the potential to be curative.”

Recent data have shown that for mesothelioma and appendiceal cancer, for which HIPEC and chemotherapy is standard of care, the five-year survival rate is now at least 50%.

Under the leadership of Dr. Mustafa Raoof, a surgical oncologist at City of Hope, the trial is being modified to include a combination of systemic chemotherapy and PIPAC for patients with colorectal and appendiceal cancer. The regimen alternates traditional chemotherapy with PIPAC.

“Unlike the first PIPAC trial we conducted, for this one, patients don’t have to have failed a previous line of therapy,” Whelan says. “In fact, they need to have been successful on the chemotherapy before we start PIPAC. We’ve started this trial, called bidirectional treatment, with five patients. We’re also looking into starting another trial for patients with pancreatic cancer.”

At City of Hope, Dellinger is developing a bidirectional trial for patients with ovarian cancer. She’s excited about this approach and believes the two types of treatments will “synergize each other.”

As with PIPAC, physicians are looking to expand the use of HIPEC beyond the two cancers for which it is commonly done. Dr. Brian Badgwell, a surgeon and oncologist specializing in gastric and esophageal cancer at The University of Texas MD Anderson Cancer Center in Houston, was the principal investigator for the three clinical trials using HIPEC for peritoneal metastases as a result gastric cancer. He has also performed over 100 HIPEC procedures to treat these metastases.

“Since the peritoneum is the most common site for metastases for gastric cancer, I would like to see HIPEC receive national guideline approval for this disease, especially since peritoneal disease is a horrible malignancy,” Badgwell says. “But progress is slow.”

Although PIPAC has provided tremendous relief to patients who have received it, the treatment
can have a negative side. Repeated treatments may cause scar tissue — or adhesions — to form, and vital organs may then cement together. As a result, they no longer function properly.

That’s what happened to Martin Greenwood, 63, of Lake Grove, New York. After receiving a diagnosis in 2020 of stage 4 appendiceal cancer that involved multiple areas throughout the abdomen,

he had surgery to remove half his stomach and 80% of his colon, along with some of his small intestine and his gallbladder, spleen, appendix and 14 lymph nodes. The surgery was followed by HIPEC, which, in his case, did not prove to be curative. Unfortunately, his cancer recurred a year later.

“At that point, PIPAC was my best option. There were only two slots for appendiceal cancer in the clinical trial, and I got the second one,” Greenwood says. “Although the PIPAC clinical trial only included three treatments, I was approved for an additional five by the FDA. I felt well and experienced a higher quality of life than I had in a while.”

Then things took a turn for the worse. Greenwood developed a series of bowel obstructions, a result of the adhesions, that required hospitalization. Because the organs were stuck together, he was not eligible for surgery.

Since then, Greenwood has had several more obstructions, occurring about a week apart. When they occur, he takes medication for the intense pain, stops eating and drinking, then moves onto liquids and soft foods before returning to his new low-fiber diet.

“I’ve managed to stay out of the hospital for over a month now,“ Greenwood says. “But I can’t afford to lose any more weight. If I can’t maintain and gain weight, I will likely have to go on TPN (total parenteral nutrition), which involves having nutrition administered through a port located in a vein near my heart. The treatment is typically administered every day and takes about 10 hours, so it would be life changing.”

While Greenwood has struggled with these problems over the last couple of months, he is grateful for the symptom- and pain-free time PIPAC gave him.

“I’ve had wonderful care at Northwell, with very compassionate nurses and doctors,” Greenwood says. “I was able to dance at my son’s wedding in 2021 and travel to Israel and Costa Rica with my wife. For that, I am forever grateful.”

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