The approval of trastuzumab (Herceptin, Genentech/Roche) for the treatment of early-stage HER2-positive breast cancer in 2006 was "paradigm-shifting," observe the authors of a new first-of-its-kind study published online August 19 in Cancer Treatment Reviews.
However, the 1-year length of treatment used in pivotal trials was chosen for "pragmatic reasons" and did not have a scientific rationale, say Bishal Gyawali, MD, of the Institute of Cancer Policy, King's College London, United Kingdom, and Saroj Niraula, MD, of CancerCare Manitoba and the University of Manitoba, Canada.
That 1-year length may be burdensome because the longer trastuzumab is used, the greater its cost, toxicity, and inconvenience, they argue.
Might a shorter duration of the heralded targeted therapy have comparable efficacy to the standard 1-year treatment period?, the pair ask.
The answer is now in: no.
In their new meta-analysis, Dr Gyawali and Dr Niraula identified four randomized clinical trials of trastuzumab (with a total of 7614 patients with early-stage disease) that employed shorter durations of treatment (ranging from 9 weeks to 6 months) and compared them to trials with a 1-year treatment period.
Pooled results demonstrated significant improvements in overall survival (hazard ratio [HR[], 1.28; P = .04) and disease-free survival (HR, 1.24; P = .005) with 1 year of trastuzumab compared to shorter durations.
"One year of trastuzumab...should remain as the standard of care," the authors conclude.
"This is an important paper," said Susan Love, MD, a breast surgeon who is the chief visionary officer of the Dr Susan Love Research Foundation in Encino, California.
"It shows that in HER2+ breast cancer more (ie, a year) may be better than less. This clearly demonstrates the importance of clinical research," she told Medscape Medical News in an email.
She explained that treatment durations are based on initial research efforts and "our best guess." After clinical use, the original approach with a drug or procedure should be "tweaked and studied," which is what happened here, said Dr Love.
Notably, the results – and the study's conclusion – are not what Dr Gyawali and Dr Niraula hoped for.
"Honestly, I was hoping secretly that putting the results together with increased power of a meta-analysis would actually provide some signal favoring shorter duration," Dr Niraula admitted to Medscape Medical News.
But the study showed that not even subgroups of patients benefited from shorter duration. For example, no statistical interaction by hormone-receptor status and node positivity on overall results was noticed (P = .73 and P = .52, respectively).
Treatment with trastuzumab has downsides, the authors point out. Up to a quarter of patients experience potentially serious adverse effects, such as myocardial toxicity. Indeed, in the new study, the odds ratio for cardiac events was 2.65 (P < .001) favoring shorter duration.
Careful monitoring of cardiac function at baseline and during treatment with trastuzumab should remain integral as part of the treatment plan," say the study authors.
A year on trastuzumab also presents the challenge of regular intravenous therapy and, last but not least, high cost.
Dr Niraula has seen up close what happens when cost limits access.
"I have personally witnessed many women in low- and middle-income countries, as well as less privileged populations in developed counties, succumb to dire cancer outcomes because of poor access to effective treatments purely due to economic reasons," he said.
In their new meta-analysis, Dr Gyawali and Dr Niraula do something that academics rarely do: they shut the door on further research.
"Our result reinforces the current practice with enhanced power of a meta-analysis and eliminates the need for further clinical studies evaluating this question," they write.
Our result...eliminates the need for further clinical studies evaluating this question. Dr Bishal Gyawali and Dr Saroj Niraula
"I think it is safe to move on now," said Dr Niraula.
Despite the study's conclusion, Dr Niraula said, "It is plausible that some treatment is still better than none.
"When the resources are constrained, shortening the duration or prolonging the frequency of drug administrations might allow women to access treatment and potentially derive some benefits, although obviously we cannot quantify any benefits from such maneuvers without evidence," he said.
Call to Promote Biosimilars
The study also raises the issue of using biosimilars to reduce costs. A US Food and Drug Administration advisory committee recently endorsed a trastuzumab biosimilar for breast cancer from Mylan GmbH for the US market. The first trastuzumab biosimilar for breast cancer was approved and introduced in India in 2013.
"Trastuzumab biosimilars have shown promising results in clinical trials that have been reported recently," said Dr Niraula. "I have high hopes that biosimilars will help narrow this drug-access gap in low- and middle-income countries, and we should all absolutely promote the use of biosimilars in such settings."
He would also like to see industry partner with various agencies to establish philanthropic programs in resource-deprived settings to allow easier access to expensive drugs.
"The enormous wealth that manufacturers of new cancer drugs have been able to accumulate should somehow be used to alleviate misery of human life where it is needed the most. Otherwise, the whole point of drug development is missed and the whole aim of scientific advancement crippled," said Dr Niraula.
The Dr Susan Love Foundation receives funding from multiple pharmaceutical companies. Dr Gyawali and Dr Niraula have disclosed no relevant financial relationships.
Cancer Treat Rev. Published online August 19, 2017. Abstract
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