Now Evidence Supports Reducing Chemo in Frail Elderly Patients

Roxanne Nelson, RN, BSN

May 20, 2019

In the largest trial so far to be conducted in frail elderly patients with advanced gastroesophageal cancer, a lower dose of chemotherapy produced similar outcomes but with less toxicity than the standard dose used for patients with this condition.

"The lowest dose tested was noninferior in terms of progression-free survival, and it produced less toxicity," commented lead author Peter S. Hall, MB ChB, MRCP, PhD, a medical oncologist at the University of Edinburgh, United Kingdom.

He was discussing the results at a press briefing ahead of the annual meeting of the American Society of Clinical Oncology, where the study will be presented.

"This is the kind of data that oncologists get excited about, and that's being able to give more tolerable treatments with comparable outcomes," said Nicholas Rohs, MD, assistant professor of medicine, hematology, and medical oncology at the Tisch Cancer Institute at Mount Sinai, New York City, who was approached for comment.

This is the kind of data that oncologists get excited about. Dr Nicholas Rohs

"This is especially impactful in a disease with a paucity of data, particularly in our elderly or frail patients that comprise a significant portion of patients with this disease," he said.

"A combination of capecitabine and oxaliplatin is a commonly used regimen in my clinic, and to know that we can reduce doses without sacrificing benefit will allow me to give this therapy to more patients than before," he said. "This may also lead to more patients being eligible for second-line therapies, as they will be in better clinical condition after finishing their first line of therapy."

Oncologists Already Lowering Doses Without Evidence

"The average age of patients at the time of diagnosis of advanced, inoperable gastroesophageal cancer is 75 years, and many are frail," Hall told reporters. "But the standard chemotherapy for this condition was developed in trials where the subjects were on average 65 years and predominantly nonfrail," he said.

Many elderly or frail patients are unable to tolerate the standard combination chemotherapy regimen, he said.

Hall explained that his team audited UK oncologists to gain insights into how they were treating this group of patients.

"Most use reduced chemo schedules to treat frail and/or elderly gastroesophageal cancer patients, but without a good evidence base to guide them," he said.

This trial is the largest so far to be conducted in this subgroup of patients, he said.

Hall and his team had previously conducted a phase 2 trial in a similar population of older, frail patients with advanced gastroesophageal cancer and found that the combination of oxaliplatin (Eloxatin, Sanofi-Aventis) and capecitabine (Xeloda, Hoffman-LaRoche) was more effective than capecitabine alone. It was also more effective than a three-drug regimen that included epirubicin (Ellence, Pfizer) in addition to oxaliplatin and capecitabine. That regimen proved to be too toxic in this patient population.

"We previously compared three-, two-, or one-drug treatments in this patient population and found two drugs were best," Hall explained.

Lowest Dose Best for Patients

The GO2 study was a phase 3 trial that included 514 patients aged 51 to 96 years who had advanced gastroesophageal cancer and were residing in the United Kingdom. The participants were randomly assigned to one of three groups. Patients in level A received oxaliplatin 130 mg/m2 once every 21 days and capecitabine 625 mg/m2 twice a day given continuously. Patients in level B received 80% of doses given to patients in level A. Patients in level C received 60% of the level-A doses.

Those with impaired renal function received 75% of the suggested doses of capecitabine.

The goal of the study was to find the optimum dosage of capecitabine and oxaliplatin for use in older or frail patients and to determine the optimal clinical benefit, tolerability, quality of life, and patient satisfaction. These factors and others were incorporated into a novel assessment tool called Overall Treatment Utility (OTU).

After 9 weeks, patients were assessed for OTU. The decision to continue therapy was based on the judgment of the physicians.

Patients in level C experienced fewer side effects and achieved better OTU outcomes than those in level A or B. This was the case even for patients who were younger and less frail.

Level C produced the best OTU results, owing to lower side effects and better quality of life for the patients who received the lower dose.

The percentage of patients who experienced nonhematologic adverse events of grade 3 or higher was 56% in both levels A and B and 37% in level C.

Survival Outcomes Similar

The secondary endpoint of overall survival was comparable among the groups: 7.5 months for level A, 6.7 months for level B, and 7.6 months for level C.

Similar time points were observed across groups for progression-free survival: 4.9 months for level A, 4.1 months for level B, and 4.3 months for level C.

Noninferiority of progression-free survival was confirmed for level B vs level A (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.89 – 1.32) and for level C vs A (HR, 1.10; 95% CI, 0.90 – 1.33).

"Noninferiority was confirmed," said Hall. "The lower doses of chemotherapy were no worse than the highest dose in terms of progression-free survival or overall survival."

The GO2 trial is the third study in the United Kingdom that has used OTU as an endpoint in this patient population. The authors suggest that the use of OTU could be a new paradigm for assessing outcomes in older populations with late-stage disease.

"Low-dose treatment may be offered to patients who are suitable for chemotherapy but too frail or elderly for a full-dose standard regimen, in the confidence that it can produce superior outcomes without compromising cancer control or survival," Hall concluded.

The authors are currently completing subanalyses of their findings and are assessing whether any one of the nine factors that constitute the OTU is dominant or more determinative regarding a patient's health.

Mount Sinai's Rohs commented to Medscape Medical News that the study seemed well done overall. He said that although metrics such as frailty can be subjective and subject to some bias, the authors did well in trying to use an objective geriatric assessment and that overall, the treatment groups seemed well balanced. "It's interesting to see that even younger, less frail patients had similar benefit/noninferiority from the lower doses and should likely be explored in further studies," he added.

"It would also be interesting to further validate OTU as an endpoint, particularly for studies such as this one," he added.

Data Needed on the Elderly

Commenting on the study for Medscape Medical News, Monica M. Bertagnolli, MD, chief of the Division of Surgical Oncology at Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, and current ASCO president, said that there are not enough data on elderly patients. "It's a big need in our profession to have more data on people who are elderly and who are frail," she said. "Most clinical trials from which we have data exclude these people deliberately because they don't want to introduce tolerability/toxicity issues."

She noted that any kind of high-quality data on the elderly is very welcome and very important. "And second, just as children are not just mini adults, the elderly are not the same as fitter younger adults," Bertagnolli said. "The older frailer are a different population. In this trial, these patients had advanced disease that could not be cured, so the issue was to find treatment that was more beneficial than harmful."

The goal is treatment that extends their life and that is not too detrimental to their quality of life, she added.

The study received funding from Cancer Research UK and was sponsored by the University of Leeds. Hall has had a consulting or advisory role (institutional) with Roche, Pfizer, and Eisai and has received research funding (institutional) from Novartis, Pfizer, Roche, AstraZeneca, and Daiichi Sankyo. Several coauthors have disclosed relationships with industry, as noted in the abstract. Rohs has disclsoed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2019: Abstract 4006. To be presented June 2, 2019.

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