Evaluating Toxicities of Antineoplastic Drug Therapeutics: Is It Time for a Critical Review?

Maurie Markman, MD

An evaluation of the utility of a cancer therapeutic in a clinical trial is determined through metrics that define 2 distinctive features of an antineoplastic strategy: efficacy and toxicity. Although that may be an oversimplification, the aim of such therapy is to improve clinical outcomes. It is therefore understandable that in most settings, there is a greater focus on the evaluation of efficacy, with toxicity often relegated to high-level and often quite subjective conclusions. For example, it is common for investigations to declare that a regimen is tolerable or to use the even more ill-defined description of well tolerated, based on unclear criteria.

It is relevant to note the relative precision used to analyze the metrics employed in an evaluation of efficacy, which can include progression-free and overall survival, as well as imaging-based objective response rates. In contrast, the multiple potential organ- and function-based toxicities are graded on scales that may appear, to some, to be compromises worked out by a large committee of cancer experts. It is uncertain that input (if any) from patients with cancer who may have experienced or been at risk to experience the adverse effects (AEs) was considered.

Crafting a Toxicity Profile

The potential for antineoplastic therapeutics to have off-target effects on organs has always been a concern. However, the magnitude of concern highlighted here is a relatively recent phenomenon In the recent past, routinely anticipated serious toxicities were most common in the hematopoietic system (ie, white and red blood cells, platelets) and the gastrointestinal tract (ie, emesis, diarrhea, stomatitis/mucositis).

The negative effects were either easily quantifiable (eg, peripheral blood counts), evaluable (eg, severity of acute emesis and diarrhea), or both. In addition, dose modifications were generally—but certainly not always—effective at reducing the deleterious effects of the therapeutic. Even the more chronic serious cardiac toxicity associated with doxorubicin was able to be reasonably predicted and the risk reduced by routine cardiac monitoring during treatment.

Therefore, it is important to inquire as to what has changed in the cancer management arena to justify the concern for the evaluation of antineoplastic drug AEs highlighted in this commentary.

First, the AE profiles of many of the antineoplastics recently introduced to the clinic are substantially different from those of the era when alkylating agents, platinum drugs, anthracyclines, and other cytotoxics were foundational in the care of advanced and metastatic cancers. For example, checkpoint-inhibiting immunological agents widely employed today have a remarkably different AE profile compared with the cytotoxic drugs they now replace or are administered in a combination regimen.¹ This statement is not to suggest this class is more toxic than the older drugs, but rather that when serious AEs develop, they are often different from those observed with these agents alone.

Another example of unique antineoplastic drug toxicity is seen with the combination of an antibody targeted to a cell receptor linked to a cytotoxic payload. Ocular toxicity, uncommonly noted as an AE of standard antineoplastic drug therapy, has been an observed prominent AE in this setting.²

Second, management of many cancers has evolved from acute care focused on the delivery of a limited number (eg, 4 to 6) of intermittently delivered antineoplastic drug courses (eg, every 3 to 4 weeks) to viewing the condition in many settings as a more chronic disease process where treatment may be continued for extended periods, possibly measured in years. Under such circumstances, more chronic or lower-grade AEs that develop or slowly worsen over an extended period or reoccur with each treatment cycle may become highly clinically relevant.

Third, the availability of effective oral antineoplastic agents delivered daily or several times each day, such as PARP inhibitors, as a maintenance strategy may pose different and particularly challenging concerns.³ For example, grade 1 nausea experienced for several days following treatment with cisplatin may be reasonably considered a major victory (and success of prophylactic antiemetic therapy), but the same grade 1 nausea experienced after each dose of a twice-a-day oral antineoplastic administered continuously for several years may be quite a different story. In fact, serious concern has been raised for the actual extent of patient adherence to many effective oral antineoplastic drug regimens.⁴

Fourth, in randomized trials examining a novel agent against a cytotoxic chemotherapeutic, the percentage of patients who experience the more serious AEs (grade 3 or 4) is often reported as a comparison between the strategies. But is this a meaningful comparison when one is comparing symptomatic events impacting organ function vs appropriately managed and largely (but certainly not exclusively) asymptomatic bone marrow suppression?

Finally, it is relevant to acknowledge that the effect of AEs on an individual’s overall quality of life in a chronologically or physiologically younger or otherwise healthier patient with cancer may be far different from that experienced by a patient with a compromised performance status. How this factor might be considered in the assessment of observed toxicity in a cancer trial is a topic worthy of discussion.

There is no intent here to criticize any pharmaceutical or biotech company in their drug developments efforts or the way observed drug AEs are discussed by clinical investigators in the oncology literature employing current standard definitions and grading scales. But is it truly rational to classify nausea that results in a “loss of appetite” or “decreased oral intake” as reported in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 that occurs after each daily dose taken for several years as being low grade?5

In a discussion with a patient who has treatment planned with an agent that may result in ocular toxicity, does a grade 2 label appear appropriate for the experience of “symptomatic” blurred vision or keratitis that is “symptomatic with medical intervention indicated” as defined in the NCI CTCAE, version 4.0?

Considering the substantial recent developments in the current management of malignant disease as well as concerns with providing optimal quality care to individual patients, is it time for the oncology community to engage in a comprehensive review of how toxicity is evaluated and graded in the conduct of cancer clinical trials?

References

1. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073-4126. doi:10.1200/JCO.21.01440
2. Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41(13):2436-2445. doi:10.1200/JCO.22.01900
3. Tew WP, Lacchetti C, Ellis A, et al. PARP inhibitors in the management of ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38(30):3468-3493. doi:10.1200/JCO.20.01924
4. Levit LA, Arora S, Kluetz PG, Magnuson A, Rahman A, Harvey RD. Call for action for improving oral anticancer agent adherence. J Clin Oncol. 2022;40(10):1036-1040. doi:10.1200/JCO.21.02529
5. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. National Cancer Institute. May 28, 2009. Updated June 14, 2010. Accessed June 28, 2023. bit.ly/3JALNq6