Oncology drug tolerance worse when used in adjuvant settings


Cancer patients may have less tolerance for targeted therapies and checkpoint inhibitors when they are used in adjuvant settings rather than metastatic settings, new research suggests.

A review of 29 oncology drugs clinical trials found that discontinuation rates due to intolerance for the same drug were sometimes almost double among patients in the adjuvant setting than in the metastatic setting, even though absolute rates of adverse effects were similar.

The review covered trials of drugs used for breast cancer (31%) melanoma and non–small cell lung cancer (17%), urothelial cancer (10%) and small cell lung cancer (7%) as well as several other less common cancers. About a quarter 24% of cytotoxic drugs and checkpoint inhibitors and half the targeted drug types (52%) were used in the adjuvant setting.

The overall discontinuation rate because of adverse events or patient withdrawal was 21.4% for patients treated in the adjuvant setting compared with a median of 15.9% in the metastatic setting (P = 0.01).

Checkpoint inhibitors showed a significantly higher rate of discontinuation in adjuvant settings compared to metastatic settings ( 21.4% vs 15.2%, P = 0.01), as did targeted drugs (27.7% vs 14.0%; P < 0.001). However, cytotoxic drugs (median rate of discontinuation, 16.6% vs 25.5%, P = 0.07) showed no difference between the two settings.

The largest differences between adjuvant and metastatic discontinuation rates were for sorafenib (renal cell carcinoma, 43.8% vs 5.5%), imatinib (GI stromal tumour, 37.4% vs 6.1%) and erlotinib (NSCLC, 37.5% vs 8.4%).

The study authors from City University New York, said the disparity in discontinuation rates supported the hypothesis that a patient’s tolerance for oncology therapies may differ in the adjuvant setting, in which drugs are administered for primarily noncurative purposes, in contrast to the metastatic, where the intent of treatment is to prevent the spread of the tumour.

They said tolerability may be less of a concern for patients if the drugs were able to improve meaningful outcomes such as overall survival. But in the adjuvant setting almost all the therapies had only shown improvements in disease-free survival, they noted.

“Patients may be less willing to tolerate the adverse effects of adjuvant treatment when they have already received what they regard as the main course of treatment for their cancer,” they said.

“In light of our findings … physicians who prescribe these adjuvant medications need to consider the patients’ reduced tolerance to adverse effects in the adjuvant setting and should engage in discussion with patients about the benefits and adverse effects when planning their treatment,” they suggested.

They also said it was notable that discontinuation rates were greater among targeted drugs, which have been used with greater frequency and for longer duration than cytotoxic drugs supposedly because of better patient tolerability.

“Our study challenges the widely held belief that targeted drugs have more favourable tolerability profiles than cytotoxic drugs. At the very least, our results suggest that the methods we use to evaluate tolerability for cytotoxic therapeutic agents may not be appropriate for the new generation of immunologically inspired agents,” they said.

The findings are published in JAMA Network Open.

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