In the development of any new therapies, the adverse effects of said therapies must always be given careful consideration. In cancer studies, for example, researchers are deeply interested in how a tumor can be shrunk down to a resectable size presurgery. The ultimate goal of any cancer therapy is to eliminate the cancer from the body completely after the therapy has been administered.
However, no such treatment yet exists for cancer. In fact, chemotherapy, the standard treatment regime for the majority of cancers today, can be so intolerable that patients sometimes opt out altogether, despite the near-certainty of a worsening prognosis.
At times, drugs have been discontinued because new research has suggested the probability of their causing adverse effects outweighs any potential clinical benefit they may confer. Imatinib is one such drug; researchers are studying whether it should be discontinued in patients with oligometastatic gastrointestinal stromal tumors (GISTs) who have undergone surgery.
GIST is a rare and deadly disease with an estimated global incidence of about 10 to 15 cases per million people. It is mainly a disease of the elderly, with the median age of diagnosis being 66-69 years. A diagnosis is made after taking into consideration the tumor’s anatomical location, its molecular features, and its immunohistochemistry patterns.
Seeking an Alternative to Chemotherapy
Importantly, “GISTs are generally resistant to conventional chemotherapy,” Kelly and colleagues wrote in the Journal of Hematology & Oncology. This eliminates one of the key tools that physicians have to fight cancer. Hence, the search for an alternative (and equally potent) drug began, leading to the US Food & Drug Administration’s approval of imatinib mesylate for the management of patients with advanced GIST in 2002.
The approval of imatinib was an accelerated process; a study indicated it was safe and effective at either 400 mg or 600 mg daily in patients with advanced GIST and authorities immediately took note. Other studies quickly followed, including one that looked at administering 400 mg imatinib once or twice a day to patients with advanced GIST. At a median follow-up of 760 days, the twice-daily dose yielded a progression-free survival rate of 56% and the once-daily dose yielded a progression-free survival rate of 50%.
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In one of the many other studies on imatinib, researchers investigated dose escalation as a possible therapeutic strategy for patients with progressive GIST. The study increased the dosage from 400 mg daily to 400 mg twice daily and the results demonstrated that 28% achieved stable disease and 3% of patients achieved a partial response.
These clinical trials gave scientists the confidence to offer recommendations that imatinib be used in GIST patients. Reichardt in Oncology Research and Treatment detailed how it is to be used:
- Imatinib is the standard first-line therapy for metastatic/advanced GIST.
- The standard dosage is 400 mg daily. A daily dose of 800 mg may be a better choice for patients with certain genetic mutations, but the optimal dosage for them has yet to be defined.
- Imatinib should be taken continuously and not be interrupted.
- As an adjuvant therapy, 3 years of imatinib treatment is recommended for patients with a high risk of relapse.
- Neoadjuvant treatment with imatinib can be prescribed for at least 6 months whenever a response would affect surgery.
- Imatinib is contraindicated if a patient has hypersensitivity to any of the active substances or excipients of the imatinib formulation.
Reichardt also provided a list of common adverse effects of imatinib, which included nausea, fatigue, myalgia, diarrhea, muscular cramps, vomiting, rashes, edema/ascites, and anorexia.
Reconsidering Imatinib in Light of Adverse Events
Many of these adverse effects are also common with other medications, but it appears that some patients with GIST report that the adverse effects they experience while taking imatinib are severe. Upon analyzing a number of studies on this issue, Fauske and colleagues concluded, “GIST patients who were receiving [tyrosine kinase inhibitor] treatment . . . experienced side effects that impacted their daily lives in both negative and challenging ways, which forced them to adapt to ‘a new normal.’”
In addition, Fauske et al discovered that patients with GIST who were taking tyrosine kinase inhibitors experienced significantly higher levels of fatigue and a lower quality of life compared to healthy controls. Clearly, the imatinib treatment regime is taking a heavy toll on some of the patients it is meant to help.
Setting aside these adverse effects, there is also concern that continuous, lifelong imatinib treatment may not be the right choice for patients with advanced GIST. In Anticancer Research, Fauske and colleagues commented, “there is substantial evidence that imatinib and other TKIs fail to completely eradicate metastatic GIST and, further, that disease progression is inevitable if imatinib treatment is discontinued.”
Hence, a bold proposal was introduced in a study: discontinuing imatinib in patients who were recipients of long-term imatinib administration and have undergone surgical resection of oligometastatic disease. This strategy is meant to eliminate unnecessary medications, ie, imatinib, and hence eliminate their adverse effects as well.
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The plan seemed to work in the study; Fauske et al reported, “Once the side effects had subsided or disappeared following discontinuation of imatinib, [the participants] reported having a surplus of energy, enjoying improved mental health and experiencing less challenges in daily life.”
This brings us back to the point made early in this article—how much care and attention do we give to the adverse effects of certain life-saving drugs? Current cancer treatment regimes, regrettably, are akin to a “scorched-earth policy”: they leave patients weaker and more vulnerable, even if they do extend life for a little bit longer. We should all hope for the day when cancer treatment is more effective and longer-lasting, with fewer life-changing adverse effects.
Kelly CM, Gutierrez Sainz L, Chi P. The management of metastatic GIST: current standard and investigational therapeutics. J Hematol Oncol. 2021;14(1):2. doi:10.1186/s13045-020-01026-6
Fauske L, Wærstad PH, Hompland I, Bruland ØS. Hope as a lifeline: imatinib discontinuation in patients with oligometastatic gastrointestinal stromal tumours. Anticancer Res. 2022;42(2):955-963. doi:10.21873/anticanres.15555
Reichardt P. The story of imatinib in GIST – a journey through the development of a targeted therapy. Oncol Res Treat. 2018;41(7-8):472-477. doi:10.1159/000487511