October 13, 2023

Maurie Markman, MD

Maurie Markman, MD, highlights the rather profound fiscal implications of the combined effect of 2 quite different but closely related components of the rapidly evolving cancer treatment paradigm.

Maurie Markman, MD

This article highlights the rather profound fiscal implications of the combined effect of 2 quite different but closely related components of the rapidly evolving cancer treatment paradigm. The first element is the recognition that it is appropriate to consider the clinical courses of several advanced malignancies as being serious, life-threatening, and frequently fatal. However, these can also be characterized more as chronic disease processes. The second is the increasing success of the efforts made by the pharmaceutical/biotech industry to develop antineoplastic therapeutics that extend survival timelines.

To begin this discussion, it is appropriate to acknowledge just how substantially clinical care in most (but certainly not all) malignancies has evolved over the past several decades. It was not that long ago when patients with what appeared to be localized or regional-only advanced solid tumors would be seen by a surgeon for resection of the lesion (if possible), perhaps followed by external beam radiation to the involved regions to enhance the opportunity for local disease control, and in a few settings (eg, breast cancer) management might include 4 to 6 total cycles of an adjuvant chemotherapy regimen every 3 to 4 weeks. If the cancer should recur or be metastatic at presentation, systemic chemotherapy might have been administered as a primary therapeutic modality, but again with a few notable exceptions (eg, lymphomas, ovarian cancer), its effectiveness was quite modest, with considerable risks for short-term distressing (eg, emesis, fatigue, stomatitis) or even fatal (eg, neutropenic sepsis, severe kidney, or cardiac dysfunction) toxicities.

In addition, even when a measurable (eg, imaging, tumor marker) or symptomatic (eg, reduction in cancer-associated pain) response was observed, in most patients such favorable developments lasted for only a few months, if not a shorter duration. Further, second-line antineoplastic drug options were even less clinically useful.

Finally, the concept of maintenance therapy, with the critical exception of certain hormonal strategies (eg, those used in managing breast cancer), was appropriately not a routine component of the oncologist’s armamentarium. For patients who experienced a response to a treatment regimen (objective, subjective, or both), prolonged continuation of treatment would almost certainly result in persistence or worsening of any adverse effects already experienced (eg, emesis with each treatment cycle, persistent hair loss) or the potential development of treatment-associated cumulative toxicities (eg, peripheral neuropathy, congestive heart failure, acute leukemia). And most relevant, phase 3 trial data supporting the survival benefits of extending treatments were lacking.

Fast forward to today. We regularly learn of phase 3 trial data that reveal the favorable survival effect of a variety of maintenance approaches to cancer management (eg, bevacizumab [Avastin] and PARP inhibitors in ovarian cancer) and the effectiveness of second-line or later treatments following disease progression after primary therapy (eg, checkpoint inhibitors in several disease settings). Further, published population-based data have confirmed the real-world impact of both early detection strategies and evolving cancer treatments on cancer-associated survival.¹ For example, earlier in 2023 the American Cancer Society reported a 33% overall reduction (“3.8 million deaths averted”) in cancer deaths from 1991.¹

Before pivoting to briefly discuss the second issue previously highlighted, that of the current antineoplastic drug development paradigm, it is relevant to note that although the successful sequential administration of antineoplastic drugs over an extended period of time (increasingly measured in years rather than months) permits an increasing proportion of individuals to experience extended survival with a satisfactory quality of life (defined by the patient), it is uncertain if government officials, health care policy makers, third-party payers, employers, clinicians, researchers, and individual patients fully appreciate the implications of this continually evolving process.

One wonders, for instance, how many patients and families would initially approach a new diagnosis of an advanced cancer with the mindset that although current therapeutic strategies may not cure the malignancy, an acceptable alternative to achieving this goal would be the possibility of prolonged sequential delivery of a variety of strategies. This may include therapies directed by tumor and liquid biopsy genomic analyses, results of imaging studies, and patient symptoms. Success in this clinical scenario would be determined by the ability to keep the cancer from progressing for an extended period with the individual able to lead a relatively normal life.

One also wonders if those involved in treatment decision-making understand that a single patented agent or combination drug regimens that might be delivered over this extended period can cost $100,000 or more per year, a figure likely to continue to rapidly rise with the passage of time.

This is not to minimize the truly remarkable contributions of individual researchers, academic teams, and numerous pharmaceutical and biotech companies that are part of the remarkable progress in both the revolutionary changes in our understanding of cancer biology and the subsequent development of beneficial novel agents. Although it is theoretically possible that the delivery of a single dose of an agent (eg, chimeric antigen receptor T-cell therapy) may result in a curative outcome, that scenario is not what is currently observed in the existing paradigm of drug treatment of advanced cancers.

The intent in writing this commentary has been to encourage an open societal discussion to encourage ideas to pursue a rational way forward, to acknowledge our evolving understanding of the remarkable complexity of individual cancer biology, to ensure continued strong pharmaceutical/biotech industry support for the development of novel therapeutics based on this biology, and to recognize the cost of required long-term treatments with increasingly expensive therapeutics.

Regardless of what one might wish to believe, the current oncology-associated drug cost trajectory is simply not sustainable. It is notable that a recently published lay press book has challenged the existing scientific focus on precision cancer medicine.² The text critically highlights alternative funding with an emphasis on environmental factors associated with disease development (eg, obesity, pollution, smoking, alcohol, social determinants, etc).² The book also includes, in some detail, the absence of meaningful economic incentives for manufacturers to lower cancer drug costs, despite the more chronic nature of the disease processes, bolstered by the opportunity for financial rewards resulting from the extended delivery times.

In conclusion, for the benefit of all current and future patients with cancer, it is essential that rational solutions to this dilemma be proposed, objectively evaluated, and ultimately implemented.

Maurie Markman, MD, is president of Medicine & Science at Cancer Treatment Centers of America, a part of City of Hope.

References

1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer Statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48. doi:10.3322/caac.21763

2. Tabery J. Tyranny of the Gene: Personalized Medicine and Its Threat to Public Health. Alfred Knopf, New York, 2023.