Hope: A Critical Concept in Oncology, but Open to Interpretation

Maurie Markman, MD

The recent rather shocking announcement from Catherine, Princess of Wales, that she was recently diagnosed with “early stages” of cancer and was undergoing “preventative chemotherapy” is a poignant reminder that malignant disease has been noted to impact an ever-younger group of individuals and that neither a favorable socioeconomic status nor fame protects against the development of this group of devastating medical conditions.¹

In the short video accompanying her public announcement, Catherine expressed a powerful and heartfelt message of hope for all who have been and will be diagnosed with cancer. The relevance of hope for individuals facing the multiple uncertainties associated with treatment and the future cannot be overstated. From the moment of confirmed diagnosis, and even preceding this event in the presence of strongly suspected signs (eg, new onset of bloody sputum in a smoker) and symptoms (eg, new and persistent localized pain and weight loss), fear for the subsequent journey, no matter how “good” the statistical prognosis, may be overwhelming.

A variety of personal strategies are called into action, including support from family and friends, as well as spiritual beliefs. The cancer community, critically including members of the clinical care team, can be of great assistance in helping the individual navigate this journey.

The impact of anxiety and fear even in the setting of “early-stage disease” may substantially negatively impact overall quality of life. For example, in a recent report of a survey of patients with localized, completely resected, “excellent prognosis” melanoma, most individuals expressed “high rates of fear of cancer recurrence.”²

In fact, the idea of emphasizing “survivorship” at the time of diagnosis, even if not without associated controversy,³ is an attempt by many to focus current and future thoughts and actions on effectively living with, and ultimately (in specific circumstances) “beating the cancer.”

While there will likely be little (if any) disagreement with the general concept of the importance of hope following the diagnosis of cancer, concerns have been raised about certain beliefs associated with this process that may result in unrealistic, even potentially harmful, expectations based on objective, statistically defined anticipated outcomes observed in others in similar clinical situations.

This topic, perhaps among the most controversial in all of oncology, has generated intense debate among cancer clinicians,⁴ ethicists,⁵ and academics⁶ regarding the degree of “unrealistic hope,” any associated serious dangers, and the suggestion that oncologists should at some level intercede to dampen what some might consider excessive optimism for a favorable response to therapy and ultimate prolonged survival based on currently available data.

For example, concern has been expressed for a lack of understanding among patients with cancer as to the purpose of clinical trials, particularly participation in early phase studies (phase 1 therapeutic trials) whose primary scientific goal is to examine safety, optimal scheduling/dosing, and pharmacokinetics rather than clinical benefit. The somewhat derogatory expression (in the opinion of this commentator) “therapeutic misconception” has been coined by members of the bioethics community to describe what are, in the opinion of these academics, common misconceived beliefs.⁷

Reports have noted the increased use of newer immunotherapeutic agents near the end of life, potentially negatively impacting a transition to palliative or end-of-life care.⁸ Does this development possibly represent in the eyes of some a relevant element of unrealistic hope?

But please carefully consider in response the powerful words of the late eminent Harvard biologist Stephen Jay Gould, PhD, who, when diagnosed with “incurable” peritoneal mesothelioma, declared the following⁹: “But all evolutionary biologists know that variation itself is nature’s only irreducible essence. Variation is the hard reality, not a set of imperfect measures for a central tendency. Means and medians are the abstractions. Therefore, I looked at the mesothelioma statistics quite differently—and not only because I am an optimist who tends to see the doughnut instead of the hole, but primarily because I know that variation itself is the reality.... The distribution [of the mesothelioma survival curve] was indeed, strongly right skewed, with a long tail (however small) that extended for several years above the eight-month median. I saw no reason why I shouldn’t be in that small tail, and I breathed a very long sigh of relief. My technical knowledge had helped. I had read the graph correctly. I had asked the right question and found the answers. I had obtained, in all probability, the most precious of all possible gifts in the circumstances—substantial time.”

How might one characterize Dr Gould’s stated perspective on his cancer diagnosis? Was this objectively unrealistic hope or a thoughtful personal decision in the face of a devastating malignancy?

Finally, I end this commentary with the published description of the first individual with non–small cell lung cancer with a ROS1 rearrangement treated with crizotinib (Xalkori), and ask the same question: Was therapy for this individual objectively unrealistic hope or a thoughtful personal decision on his part (with guidance from the clinical team) in the face of a devastating malignancy?¹⁰

“The patient is a 31-year-old male never-smoker diagnosed with multifocal bronchioloalveolar carcinoma in August 2010. Genetic testing of his tumor demonstrated no EGFR mutation or ALK rearrangement. He was treated at an outside institution with first-line erlotinib [Tarceva] with no response. As a result of progressively worsening symptoms and hypoxia, he was referred to Massachusetts General Hospital for additional genetic testing and was found to be ROS1 positive. On April 20, 2011, the patient was started on crizotinib at the standard dose of 250 mg twice daily. In less than 1 week, he noted a significant improvement in symptoms, and by 2 weeks, his hypoxia had resolved. Restaging at 8 weeks demonstrated near complete resolution of his multifocal lung tumor, which was subsequently confirmed at 12 weeks. At the time of this report (6 months), the patient continues on crizotinib with no evidence of recurrence.”

References

1. Colchester M, Luhnow D. Kate Middleton, Princess of Wales, being treated for cancer.Wall Street Journal. March 22, 2024. May 27, 2024. https://www.wsj.com/world/uk/kate-middleton-cancer-
   announcement-bc049f65
2. Mahama AN, Haller CN, Labrada J, et al. Lived experiences and fear of cancer recurrence among survivors of localized cutaneous melanoma. JAMA Dermatol. 2024;160(5):495-501. doi:10.1001/jamadermatol.2023.6158
3. Astrow AB. A piece of my mind: cancer survivorship and beyond. JAMA. 2012;308(16):1639-1640. doi:10.1001/jama.2012.13258
4. Tripp P. Never take hope from the patient. The American Scholar. February 12, 2022. Accessed May 27, 2024. https://theamericanscholar.org/never-take-hope-from-the-patient/
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7. Henderson GE, Churchill LR, Davis AM, et al. Clinical trials and medical care: defining the therapeutic misconception. PLoS Med. 2007;4(11):e324. doi:10.1371/journal.pmed.0040324
8. Canavan ME, Wang X, Ascha MS, et al. Systemic anticancer therapy at the end of life- changes in usage pattern in the immunotherapy era. JAMA Oncol. 2022;8(12):1847-1849. doi:10.1001/jamaoncol.2022.4666
9. Gould SJ. The median isn’t the message. Virtual Mentor. 2013;15(1):77-81. doi:10.1001/virtualmentor
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10. Bergethon K, Shaw AT, Ou SHI, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30(8):863-870. doi:10.1200/JCO.2011.35.6345