Hope and Uncertainty in the Age of Miracles

Uncertainty is an uncomfortable position. But certainty is an absurd one.

—Voltaire

When nothing is sure, everything is possible.

—Margaret Drabble

“I want what jimmy carter got” he said, newspaper clipping on his lap. His wife nodded imploringly, her hand encircling her husband's wrist, looking up with trepidation. In my clinic of solid tumor patients, not a few days go by without someone bringing up the former President and his astonishing remission from cancer.

Whenever I am asked about Jimmy Carter, my mind wanders to a moment in residency when I was standing in the hospital room of a very young man who was from my hometown, my high school. His wife, parents, and young daughter were at the bedside, and his lungs were drowning in melanoma. In the time before checkpoint inhibitors and potent targeted therapy, there was nothing more to offer.

While we were in that room, checkpoint blockade was already in development. Today, a 90-year-old man with brain and liver tumors can go on to what seems to be very close to the definition of a miraculous recovery. No wonder every patient wants what Jimmy Carter received. Certainly every oncologist wants to be the physician to deliver it. Every patient is hoping for hope, and a chance to continue a quality life. We oncologists are hoping too, and with good reason. With every new drug approval, Kaplan–Meir curves with the ever more enticing tails, and swimmer plots that seemingly swim forever, oncology has clearly entered a different era.

I first felt the full potential of these new possibilities when I met a young man with an unusual type of widely metastatic kidney cancer. An avid traveler in his early thirties, he was in a wheelchair the first time we met, on high doses of narcotics and still in pain, not able to work and having rapidly progressed on several lines of standard therapy. Although other approved options were available, we petitioned a pharmaceutical company for a checkpoint inhibitor that was not approved for his cancer, arguing that no other standard therapy was likely to work. Incredibly, after just two doses, he was feeling better, off pain medication, his breathing improved, the palpable subcutaneous nodules melting away. ¹ Now, more than two years later, he is working full time, living in a newly purchased home, exercising daily, and vacationing with his wife. He still comes every few weeks for his infusions, and we worry about the vacillating lymph nodes in his chest. His wife still looks petrified at every visit, waiting for bad news to arrive. But his mother no longer accompanies them, and this year he and his wife are planning their first international trip since the diagnosis.

Immunotherapy, targeted therapy, and genomic profiling, are fundamentally changing the care of cancer patients and are poised to continue to do so over the ensuing decades. They can extend lives meaningfully for months to years. However, new therapies do not work for everyone. The durability of their efficacy is highly variable, and their side effect profile can be unpredictable. For immunotherapy, the side effects are sometimes devastatingly furious.

Furthermore, we do not yet have reliable tools to predict response to immunotherapy. As a result, patients are left guessing, hoping for the miracles they have heard about, unsure whether they will be the lucky one. But to be clear, I am now hoping right there with them. The palliative care adage—“hope for the best, but prepare for the worst,”—has taken on a different meaning for both patients and physicians. ² Before, I would have a clear point at which I would work to redirect hope. To hope for quality in a person's remaining time, to hope for a family coming together. Now some of these approved drugs feel like the ultimate wild card. Although the odds are sometimes low, I am never sure anymore when the patient in front of me will get the lucky draw and have a deep and lasting response. For an oncologist this is both exciting and invigorating. It leaves me more optimistic and energized at the end of a difficult day, affording me more hope on behalf of my patients than I have ever had. At the same time, perhaps more so than ever before in oncology, I find it difficult to thoughtfully prognosticate in this rapidly evolving therapeutic environment. ³

Buttressed by my success with my first immunotherapy success, I was optimistic when discussing immunotherapy with yet another young man. His cancer was in many ways similar—histologically almost identical, poorly differentiated, and terribly aggressive. I hoped that the ugly tumor had lots of mutations, spreading its neoantigens like fireflies in the summer breeze, begging for checkpoint blockade. Every few weeks as I prepared to knock on the exam door, I would hold my breath, waiting to hear that the pain is all of a sudden diminished and the appetite picked up, only to find no such news. After a few months we had to admit that the drug was not working, no miracle was in sight. My patient was too weak for more treatment and died soon thereafter in hospice. Although I knew that the chances were long from the start, I felt let down and angry—it did not seem fair that the same drug would lead to such drastically different responses in such seemingly similar clinical scenarios.

In between these opposing examples, there are now many patients for whom novel therapies have created a new phase of disease—“chronic” advanced cancer. This has already occurred for many patients with both hematologic and solid malignancies such as chronic myeloid leukemia, multiple myeloma, prostate, and breast cancer. Given the expected rise of cancer incidence, the prevalence of survivors (based on multiple national organizations, survivorship begins with the diagnosis of cancer) with advanced cancer will also increase. ⁴ Simultaneously, treatment options for advanced cancer patients are rapidly evolving with oncologists becoming constant gardeners, “pruning the phylogenetic tree” ⁵ of sub-clone mutations, sprinkling in some reinvigorated T-cells. The advent of novel therapies and the subsequent movement of cancer toward a chronic disease may mean that I no longer have to hope for the best but plan for the worst. There is a middle ground, and that middle ground can last for years.

New hopes for longer-term survival lead to a number of questions. How should clinicians discuss prognosis with patients in the setting of a rapidly expanding therapeutic armamentarium and a wide variation in often-unpredictable outcomes? Should every advanced cancer patient be offered immunotherapy, even if not proven for their particular indication, and if not, how do we compassionately break that news to patients? And if our efforts are successful and more patients move to a model of chronic disease, what are the needs of patients on chronic therapy for an incurable cancer? What is required of oncologists, oncology practices, and cancer centers as they try to meet those needs? Table 1 summarizes potential challenges and opportunities for patients and clinicians dealing with advanced cancer.

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Table 1.

Comparison of a Traditional and an Emerging Paradigm in Advanced Cancer Patients with Respect to Patients, Caregivers, Physicians, and the Healthcare System

Factor	Traditional paradigm	Emerging paradigm	Potential challenges and needs	Potential solutions and areas of investigation
Prognosis and opportunities for “Goals of Care” and “Advanced Planning” discussions	Life-expectancy is variable, but generally shorter; sometimes very short	Life-expectancy is variable, but generally longer; much longer for a substantial minority of patients	Ability to accurately and compassionately prognosticate and set expectations; uncertainty for all stakeholders	Specific and recurring training for physicians on communication in serious illness
	Opportunity for discussions exists but sometimes dealing with rapidly evolving clinical challenges precludes in-depth discussions until late in the disease course	Potentially much more opportunities for advanced planning discussions leading to improved end-of-life transition	Ability to plan for upcoming life events	Ongoing collaboration with pain and palliative care colleagues and expansion of palliative care services
				Practice and center wide programs to support patients via social work and peer groups
Uncertainty and psychological distress	High, but often short-lived	Variable, likely high-moderate, but chronic	Chronic anxiety	Training for providers and opportunities for patients to engage in psychological support, yoga and mindful meditation, exercise, journaling, CBT programs, peer support programs
			Chronic depression
			PTSD symptoms
			Distress for partners, children and friends
				Pharmacologic interventions
Physical symptoms	A variety of physical symptoms, frequently acute and severe	Chronic pain, fatigue and low to moderate-grade adverse events	Long-term management of low-to-moderate grade adverse events	Ongoing collaboration with pain and palliative care colleagues
		Concern over sexuality and fertility	Young adults with an incurable cancer becoming parents	Refresher courses on management of symptoms for oncology providers
		Risk of second malignancy	Sexuality while on chronic anti-cancer therapy	-Integrative medicine programs
Cost of care, financial burdens to patients and the healthcare system and work productivity	Cost of care is high	Potentially very high due to more visits, tests, referrals, cost of drugs and missed work (e.g., one year of immunotherapy or targeted therapy may cost the healthcare system ∼$100,000)	Ability to pay for prolonged treatment courses	Financial counselors
	Work productivity is very low		Financial planning for an uncertain future for the patient and their family	Cost-effectiveness analysis, clinical pathways, value-based insurance design, goals of care discussions
			Unclear expectations for ability to return to work and stay employed	Dialogue with employers about limitations of patients
		Work productivity higher, potentially much higher with some patients working full time	Support for part-time employment; work with chronic toxicity
Visits to the oncology clinic and need for nonphysician oncology providers	Variable, with some utilization of nononcology physicians	More visits to the oncology clinic, sometimes much more (every two to three weeks for years)	Specialists other than oncology providers may not be aware of mechanism of action, side-effects, interactions	Greater utilization of nonphysician providers (PAs, NPs).
		Potentially more visits to nononcology providers as long-lasting and new side-effects of treatment can lead to more need for nononcologic expertise and referrals	Increasing burden on patients and caretakers	Development of oncology care homes/models with a group of nononcology providers (cardiologists, nephrologists, endocrinologists, psychologists) who are invested in the care of cancer patients

CBT, cognitive behavioral therapy; NPs, nurse practioners; PAs, physician assistants; PTSD, post-traumatic stress disorder.

My patient who wanted what Jimmy Carter got has not gotten it, but he asks me about it on a regular basis, and maybe one day he will. We do see each other a lot. As is often the case with oncologist and advanced cancer patients, I have become a focal point of his care and in some ways his primary care provider. The oncologist–patient relationship is now taking on an expanded meaning as our sickest patients live for a long time, allowing for even deeper and more meaningful relationships. Navigating these shifting waters of chronic treatment of advanced cancer and perhaps potential cures in the future is exciting, and it gives me hope.