Weekly Dose-Dense Chemo Not Recommended in First-Line Epithelial Ovarian Cancer Treatment

By Matthew Fowler

Weekly dose-dense paclitaxel as a frontline treatment for patients with epithelial ovarian cancer was not found to significantly improve progression-free survival (PFS) compared to the standard 3-weekly chemotherapy, according to results from the ICON8 study published in The Lancet.¹

“The results of the ICON8 trial show that it is feasible to deliver weekly dose-dense paclitaxel in combination with either 3-weekly or weekly carboplatin in the first-line treatment of high-risk ovarian cancer,” Andrew Clamp, PhD, of The Christie NHS Foundation Trust, and colleagues wrote. “However, neither of these regimens is associated with an improvement in survival outcomes compared with standard 3-weekly carboplatin–paclitaxel treatment in the predominantly European population treated on this trial.”

The phase III ICON8 trial randomly assigned predominantly European women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC–IV epithelial ovarian cancer to 3 groups.

1,566 women from June 2011 to November 2014 were recruited for treatment as a part of the ICON8 study. In this 3 arm trial, patients in group 1 received carboplatin AUC5 or AUC6 and 175 mg/m²paclitaxel once every 3 weeks; patients in group 2 received carboplatin as in group 1 and dose-fractionated 80 mg/m²paclitaxel weekly; and patients in group 3 received carboplatin AUC2 and 80 mg/m²paclitaxel weekly.

Primary endpoints for the study were PFS and overall survival (OS). Both groups 2 and 3 were individually compared with group 1 (control group) to determine primary endpoint results. Secondary endpoints included safety, quality of life, and health economics.

The median PFS was 17.7 months for the control group (group 1), 20.8 months in group 2, and 21.0 months in group 3.

After a 9-month cross-analysis of the results, the study determined there was no significant difference between the groups with regards to quality of life. As for toxic effects, both group 2 and group 3 treatments were associated with increased instances of grade 3 or higher toxic effects, but these effects were deemed “uncomplicated.”

“Although most patients were able to complete 6 chemotherapy cycles, both weekly treatments were associated with more treatment modifications and a higher incidence of grade 3 or higher toxic effects,” stated in a press issued by the European Society for Medical Oncology (ESMO). “Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated.”²

The population included both patients who underwent primary cytoreductive surgery (IPS) and those who chose delayed primary cytoreductive surgery (DPS) options. The results from each of these populations also stood as a secondary point of intrigue for the researchers. No significant relationship between surgical decision and treatment schedule was detected.

The ICON8 study was a large, international process including a variety of different patient variables, including demographic, surgery selection and treatment schedule. The study also yielded an 85% chemotherapy completion rate, allowing for valuable results to be drawn from the process. Even more, although the results did not yield a positive development for European women, the weekly-dose treatment can still be an option for Japanese women with epithelial ovarian cancer, who previously demonstrated a superior benefit to the regimen.²

“Weekly dose-dense paclitaxel treatment could still be considered as a first-line treatment option for Japanese women with epithelial ovarian cancer,” said in an ESMO press release. “But the weekly dose-dense paclitaxel should not be recommended as a component of first-line epithelial ovarian cancer treatment for women of non-Japanese ethnic origin.”

Two further studies have been done analyzing weekly dose-dense chemotherapy treatment within the lifetime of the ICON8 study, but the researchers recommend even more investigation into this treatment among different ethnic groups.

This article was published by Cancer Network.

Endometriosis Appears to Have No Effect on Ovarian Cancer Outcomes, But More Research Needed, Study Says

By Marissa Wexler, MS

Endometriosis does not seem to significantly affect ovarian cancer prognosis and survival in patients of reproductive age, a small study suggests.

However, more research is needed to identify factors associated with the progression of endometriosis to cancer and also to identify women who would benefit from more aggressive endometriosis treatment.

The study, “Endometriosis-associated ovarian cancer is not a distinct clinical entity among young patients: A 12-year cohort study,” was published in the European Journal of Surgical Oncology.

Ovarian cancer risk factors include a number of variables, such as age, weight, menstrual history, pregnancy history, smoking, inheritance of certain mutations, and benign gynecological conditions, including endometriosis.

Specific risk incidences vary depending on the type of cancer, but according to a study published in The Lancet, overall, endometriosis was estimated to increase ovarian cancer risk by nearly 50%.

However, it remains unclear whether there is a meaningful clinical difference between ovarian cancer in a person with endometriosis (endometriosis-associated ovarian carcinoma, EAOC) and the same type of cancer in a person without endometriosis (non-endometriosis-associated ovarian cancer, non-EAOC).

This is of particular interest in younger individuals, since age itself is independently associated with different ovarian cancer prognoses (younger age seems to be a prognostic factor for improved survival). Moreover, endometriosis is most common in people between 25 and 35 years old, according to the authors of the study.

The researchers analyzed medical records of people 40 years of age or younger who were treated for ovarian cancer at the Peking Union Medical College Hospital in China between 2006 and 2017.

Specifically, the researchers compared cases of EAOC, comprising either ovarian endometrioid carcinoma (OEC) or ovarian clear cell carcinoma (OCCC), with non-EAOC cases.

The studied group included 94 people with ovarian cancer — 40 with endometriosis (EAOC group) and 54 without (non-EAOC group). All of them were treated surgically; most also received chemotherapy.

In terms of outcomes, “a total of 77 (81.9%) patients were alive with no evidence of residual tumour at the time of the last visit, 4 (4.3%) patients were alive with the recorded disease, and 13 (13.8%) were dead of the recorded disease. There were no obvious differences between the two groups in terms of these variables,” the researchers wrote.

Further statistical analyses demonstrated that endometriosis was not significantly associated with an altered risk of disease progression or death. Another factor was, most notably, whether there was residual disease after initial treatment.

On the whole, there were “no differences in clinicopathological [disease-causing] or prognostic features,” between ovarian cancer in people with or without endometriosis, according to the researchers.

There was one exception: painful periods, or dysmenorrhea, which was reported by a much higher percentage of people with endometriosis than without (45% vs. 3.7%). But, the researchers said, this “is a typical symptom of patients with endometriosis,” and, as a result, most likely isn’t tied to the ovarian cancer.

This was a fairly small study of patients treated at a single center, so the results shouldn’t be generalized yet — there is still a need for further research to understand both endometriosis and ovarian cancer, and the intersection of both diseases.

“Endometriosis is not an independent prognostic predictor in patients with OCCC and OEC when age is confined to under 40 years. It is premature to consider ovarian cancers arising from endometriosis as a distinct entity,” the researchers concluded.

“This analysis also suggests that reproductive-aged women with early-stage OEC and OCCC should be offered conservative treatment,” they said. “Future research should focus on the identification of factors that are associated with the malignant transformation of endometriosis and how to identify women for whom more definitive endometriosis treatment would be appropriate to prevent ovarian cancer.”

This article was published by Endometriosis News.

Small, Thin Metal Mesh Loaded With T Cells Shrinks Tumors in Ovarian Cancer Models

What if a metal that’s already used to repair broken bones, straighten teeth and keep arteries from clogging could also be used to stop your cancer from spreading?

New findings published Dec. 9 in Nature Biomedical Engineering from scientists at Fred Hutchinson Cancer Research Center show for the first time that a piece of small, thin metal mesh loaded with cancer-fighting immune cells shrinks tumors in preclinical models of ovarian cancer.

Cell therapies to fight cancer have had great success in blood cancers but haven’t worked well with solid tumors. Our findings take a significant step toward making cell therapies effective against solid tumors by showing that a thin metal mesh loaded with T cells engineered to fight ovarian cancer cleared tumors in 70% of the treated mice.

Lead author Dr. Matthias Stephan, a faculty member in the Fred Hutch Clinical Research Division

Solid tumors, including cancers of the breast, ovary and pancreas, have a variety of tactics to hide from and fight back against cancer-killing immune cells like CAR (chimeric antigen receptor) T cells. Simply injecting anti-cancer cells has not worked; they don’t reach the tumor or if they do reach the cancerous cells, they tire out in trying to kill them and are then shed from the body.

Stephan designs materials that are safe in the body and can carry cancer-fighting cells to tumors. “In addition to minimizing side effects in patients, our ultimate goal is to make T-cell therapies faster and cheaper to make, and easier to deliver to patients.” he said.

In a step toward that goal, Stephan’s latest study loaded CAR T cells targeting ovarian cancer onto a porous, mesh-like metal film and then placed the film on tumors.

“This is not just a passive delivery device,” Stephan said. “It’s a release platform that triggers an expansion of CAR T cells that can overcome defenses that tumors make against the immune cells.”

The researchers used thin, nearly translucent metal films made by Monarch Biosciences (MonarchBio), which helped fund the project. The films are 10 micrometers thick, which is 1 millionth of a meter, or about seven times thinner than the average width of a human hair. Made of nickel titanium, the film can safely be implanted within the body and is used in other medical devices.

Viewed under a powerful microscope, the film has minuscule spaces that can be configured into different patterns. The spaces can be filled with drugs or other liquids and then implanted in the body, where the liquids ooze out and find their targets.

Stephan and his colleagues wanted to see if the films could hold T cells and deliver the cancer-fighting cells to tumors.

“We needed to find a pattern of the film that would work well for T cells,” Stephan said. “The pattern needed to be small enough where the cells would not fall between the cracks and not too small so that the T cells would feel too cramped and wouldn’t be able to move.”

They found that a pattern with straight lines resembling a top-down view of a maze worked best with the T cells. They coated the metal film with a combination of materials that allow the CAR T cells to grow and expand once they’re in the body.

The Fred Hutch team loaded the film with CAR T cells programmed to seek out a marker for ovarian cancer cells, called ROR1. The engineered cells were placed on both sides of the film and were then absorbed into the middle of the material.

“It’s like a piece of bread spread with marmalade on both sides,” Stephan said. “The metal film is the bread, and then we put CAR T cells on both sides of it and then they soak into the middle too.”

Using lab models of ovarian cancer, the researchers implanted films loaded with CAR T cells on the tumors. The T cells moved out of the film and gravitated near the tumor. Within 10 days, the tumors disappeared in all mice. Within 20 days, 70% of the mice remained tumor-free.

The approach — if confirmed by more studies and clinical trials — could eventually be used to treat diseases such as pancreatic and ovarian cancer, where tumor growth could be kept in check by implanting the film over it.

In another experiment reported in the same paper, the Fred Hutch researchers found that a tube-like version of the film soaked with CAR T cells kept tumors from growing into the tube. This approach could be used in cancers that cause obstruction of the airways or the digestive system, such as lung cancer or pancreatic cancer, or esophageal cancer, where stents are used to restrain tumors from interfering with swallowing.

“We focused on CAR T cells in the current experiment, but I could see this approach working with T cell receptor therapies, natural killer cells and other types of immune cells that target cancer,” Stephan said.

This article was published by News Medical.