Cancer Staging and Toxicity Framework Should Be Overhauled for the Modern Era

Maurie Markman, MD

The management and outcomes for a large proportion of advanced cancers have changed rather substantially over the past 10 to 20 years. It was not that long ago, for example, when standard therapy for metastatic lung cancer was simply cytotoxic chemotherapy and the only relevant distinction in the agents used was the division between small cell and non–small cell lung cancer. Formerly, small cell lung cancer was generally considered more chemotherapy sensitive in the short term but also associated with an overall inferior survival outcome; however, the difference in prognosis compared with metastatic non–small cell lung cancer was measured in months—rarely longer.

Terms such as cure or even prolonged survival were rarely used when discussing the vast majority of advanced, metastatic, or recurrent solid tumors. In general, when employing cytotoxic chemotherapy during this era, the realistic goals of the therapeutic regimen were limited extension of overall survival, palliation of existing symptoms, or prolongation of the time to subsequent disease progression or development of symptoms. Of course, there were important exceptions to this distressing status quo, such as patients with advanced germ cell tumors (both male and female) and, occasionally, patients with epithelial ovarian cancer, who would achieve extended disease-free survival.

Further, antineoplastic therapies (excluding hormonal manipulations such as in cancers of the breast and prostate) were often quite brutal in their short-term effects, including substantial emesis and other effects on the gastrointestinal tract, fatigue, and bone marrow suppression. In addition, more long-term, potentially devastating toxicities, including cardiomyopathy and peripheral neuropathy, were not rare. It was not uncommon for patients to simply decline suggested treatments as the cancer worsened, in view of the toxicities they had already encountered or were likely to experience with additional drug delivery. Treating oncologists commonly heard statements such as “chemotherapy is worse than the cancer” and “life is not worth living if I take these drugs.”

In the early days of the modern oncology era, it was often appropriate to suggest that the only realistic chance for cure was surgical, with local radiation adding a relevant component to prevent local tumor spread and morbidity. If chemotherapy was indicated, the prognosis for solid tumors—with a few relevant exceptions—was dismal.

This was the state of affairs when 2 universally used standard definitions and terminologies were introduced and subsequently became foundational for the entire field of oncology: the cancer staging system and the toxicity scales routinely employed in clinical trials.

One can certainly understand the goals and utility of this framework in a clinical universe where solid tumors are either cured (or not) through surgical removal, and where the presence of metastatic disease discovered at initial diagnosis or at a subsequent point in time in the natural history of a cancer is characterized by short-term survival (measured in months, if not weeks). One can understand all this when antineoplastic therapy is delivered rather briefly in view of both its limited effectiveness and serious adverse effects, and where the realistic hope associated with the introduction of a new therapy would be to permit patients to extend their survival, albeit modestly.

Shortcomings of the Current Standards

The critical question now is whether the existing cancer staging system and the standard toxicity scales accurately reflect cancer management in 2021 and beyond and, to be blunt, whether the current system has outlived its usefulness.

First, let us consider cancer staging. This well-established and meticulously defined system is foundational in cancer management and is a core component in defining both prognosis and treatment. However, the fact that the formal process of staging is undertaken once, and only once, during the natural history of a patient’s cancer journey is increasingly problematic. Many cancers are being appropriately viewed as chronic conditions, where the patient’s ultimate survival even when surgical cure is not possible may be measured in years rather than months or weeks.

In fact, the current staging terminology is increasingly unhelpful and can be confusing to clinicians and patients alike. A given cancer may locally or regionally recur or metastasize after, for example, initially being staged as a localized mass (stage 1) with no lymph node involvement (eg, T2, N0, M0) but that cancer does not now become characterized as stage 4 due to documentation of tumor spread. The common use of the expression restaging only complicates the confusion with existing terminology, because patients may believe their cancer now has been defined as being of a different stage. Establishing more precise, universally accepted terminology for specific events that may occur during the cancer continuum and include several potential phases would help to enhance communication among oncologists, clinicians not focused on treating cancer, and patients. These terms could include observation; adjuvant, neoadjuvant, consolidation, and maintenance drug delivery; local, regional, and distant recurrences; and primary and multiples lines of antineoplastic therapy.

Similarly, the widely accepted common toxicity scales are focused on the periodic administration of antineoplastic agents that are often associated with sudden, sometimes severe, but generally intermittent effects that disappear or at least substantially improve prior to the next treatment course. Emesis, for example, is graded based on the severity of acute events beginning after the administration of an antiemetic agent. Even when therapy is delivered over several days, such as cisplatin given in a 5-day regimen in the treatment of germ cell tumors, the toxicity scale suggests that adverse effects will improve relatively rapidly or gradually over a period of hours, a few days, or several weeks in more severe circumstances.

But what happens when therapy becomes more chronic? This is increasingly the situation with maintenance strategies used in a variety of clinical settings, in which treatment is delivered 1 or more times a day for months or even years. Under these circumstances, what does it truly mean to state that a patient is experiencing low-grade nausea?

Regarding intermittent drug delivery, such a symptom reported to last for several days on an every-3-week treatment cycle may be quite acceptable. But what if “low-grade nausea” occurs after each oral dose, and persists for several hours every day for as long as the drug is administered? Is it appropriate to use the same toxicity label to describe what patients are experiencing in this situation as with standard intermittent drug delivery?

The cancer staging system and toxicity scales have been enormously useful in the development of modern oncology, but perhaps it is time to consider modifications to reflect a substantially altered cancer clinical arena.