That might soon change with the publication of a unique study. Lasting 10 years, the phase 3 STAR trial involved 920 patients across 60 cancer centers. These patients had advanced kidney cancer and were taking either sunitinib (Sutent) or pazopanib (Votrient).
The results showed that taking an occasional respite from TKI therapy had little impact on the patient’s survival.
The study was published online in The Lancet Oncology.
The study was funded by the United Kingdom’s National Institute for Health and Care Research because drug companies never run studies on how to reduce the use of their drug, commented lead author Janet Brown, MD, of the University of Sheffield (England).
“We rely on the NIHR to do these important trials that … companies wouldn’t do,” she commented to this news organization.
Commenting on the rationale for STAR, coauthor Jenny Hewison, PhD, of Leeds (England) University School of Medicine, explained that patients often find it difficult to tolerate TKIs. “Although these patients are getting the best treatment that we can offer them, it’s very demanding. … It could make them feel tired, quite unwell. And there can be a range of other effects including sickness and diarrhea.”
As an example, 77% of patients in the pivotal trial of sunitinib in kidney cancer experienced grade 3 or 4 adverse events such as hypertension (13%), fatigue (15%), diarrhea (10%) and hand-foot syndrome (8%).
Both sunitinib and pazopanib carry label warnings of severe and fatal hepatotoxicity.
Also, in contrast to conventional chemotherapy, which is usually given in a finite number of courses, treatment with TKIs carries on indefinitely.
“It feels like you’re taking [TKIs] for the whole of the rest of your life,” said Dr. Brown.
Study details
The STAR trial, an open-label, noninferiority, randomized controlled study, is the first phase 3 study of treatment breaks in renal cell carcinoma. The participants had inoperable locoregional or metastatic clear cell renal cell carcinoma (ccRCC) and had received no systemic therapy for advanced disease.
They were randomly assigned before TKI treatment to a conventional continuation strategy or a drug-free interval approach. The treating physician decided whether a patient would take sunitinib or pazopanib.
All participants took their drugs for four cycles (6 weeks each cycle). At the 24-week point, those with a complete response, partial response, or stable disease began their randomized assignment.
Individuals who took a break continued until their disease progressed, at which point therapy was resumed. They could take further treatment breaks once their disease was back under control. The group on continuous treatment kept going until disease progression or intolerable toxicities. Median follow up was 58 months.
In both the per-protocol and intent-to-treat (ITT) populations, overall survival was 28 months for the people who received continuous treatment vs. 27 months for those who took a break. Statistical noninferiority was established in the ITT population but not in the per-protocol population.
The median length of all treatment breaks was 87 days. Many people took two or more breaks; one patient took nine breaks overall. The breaks were popular: only 3% of participants who were meant to stop therapy withdrew from the study in order to continue their treatment.
Said Dr. Hewison: “In the very early days of planning the study there were some doubts as to whether it would succeed because of potential unwillingness of people to stop treatment for a while.”
Dr. Brown agreed: “People did worry about that initially, but it actually seemed to be more the other way around. By that time – 6 months – people were relieved to be there. …We actually had some people from the other arm asking, could they also have a break?”
To understand better the benefits of treatment breaks to patients, Janine Bestall, PhD, a senior research fellow in applied health research at the University of Leeds, conducted a qualitative study in parallel with the main trial.
Summing up the patients’ experiences, Dr. Bestall said the drug-free periods “gave them more time.”
Dr. Bestall quoted one patient who said: “I know that things can happen and it grows back, but you’ve always got the buffer there knowing that you can go back and get help. But you actually lead a normal life and the advantage is, yeah, you can go on holiday, you can actually do more things in the garden, cleaning up, painting, whatever needs doing, you do it.”
Dr. Brown said, “I had a lady who, when she was on the trial, had four breaks in total, one when her daughter got married, and [she said] that was really nice for her to do all the shopping and all the normal things that you do, and not be on something that was making her tired and causing sore hands and diarrhea.”
The drug-free interval strategy provided annual cost savings of 3,235 pounds sterling ($3,850) and a noninferior quality-adjusted life-year (QALY) benefit in both the ITT and per-protocol populations.
Serious adverse reactions occurred in 9% of patients in the treatment-break group versus 12% of the continuous-treatment group.
The authors of the study concluded, “Treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma.”
