Prospect of Cure in Cancer Care

Nature of Cancer Cure

The American Cancer Society recognizes three main goals of chemotherapy: cure, control, or palliation. With respect to cure, patients are informed that “if possible, chemo is used to cure cancer, meaning that the cancer is destroyed—it goes away and doesn't come back. Most doctors don't use the word “cure” except as a possible or intended result of treatment that might have a chance of curing a person's cancer, the doctor may describe it as treatment with curative intent. Although cure may be the goal in these situations, and is the hope of many who have cancer, it doesn't always work out that way. It often takes many years to know if a person's cancer is really cured.” ¹

A 2020 comprehensive perspective on the changing treatment landscape of cancer in the United States mentioned the word “cure” only once, remarking, in the conclusion, that “an increase in survival rates among many patients with cancer and cure in some.” ²

Cancer is a heterogeneous multisystem disease, and its management through multidisciplinary tumor boards involves many diverse specialists. This article explores the nature of cancer cure through the eyes of patients, carers, oncologists, and other clinicians, and it includes the viewpoint of medical philosophers, to probe the essence of the prospect of cure in the care of advanced cancer.

Oncology clinicians report that patients are hesitant to ask whether they are cured, and the clinicians are hesitant to tell patients that they are cured. ³ Use of the word “cure” in cancer care reflects a balance of physician and patient optimism, realism, medico-legal concerns, and even superstition. The euphemisms “complete remission,” or “no evidence of disease” reflect the current inability to precisely determine whether cancer is ever truly, completely gone. In other words, the patient is off therapy and their chance of dying of that malignancy is no greater than someone in the general age-matched population. Whenever we talk to a patient about the prospect of a cure of their cancer, we must be very clear that we can never be absolutely sure in any individual case.

Doctors often fear that, by expressing uncertainty, they will project ignorance to patients and colleagues. However, the reality is that doctors continually have to make decisions on the basis of imperfect data and limited knowledge, which leads to diagnostic uncertainty. This is coupled with the uncertainty that arises from unpredictable patient responses to treatment, and from health care outcomes that are far from binary. ⁴

New cancer therapies are altering the paradigm of cancer care. However, although survival may be prolonged, most patients with an advanced cancer diagnosis face an incurable illness. Such patients often fail to understand their prognosis and the goals of treatment, and these misperceptions are associated with poor patient outcomes, including inappropriate aggressive care at the end of life. ⁵ The challenge of prognostic uncertainty is not new. Sir William Osler decreed that “medicine is a science of uncertainty and an art of probability.” ⁶

Innovative strategies may be required to provide patients and their families with the means to navigate the psychosocial sequelae and uncertainties inherent in the recent advances in cancer therapeutics. We could perhaps reduce everyone's discomfort by reframing uncertainty as a surmountable challenge rather than as a threat. Philosophically there is an apparent paradox in dealing with uncertainty; we want to reduce uncertainty, but we do not want to eliminate it totally. Only because we do not know what the future holds can we have our hope and choices. ⁷

In the context of informing patients about the effects of treatments with curative intent, there is an implied acceptance that uncertainty exists. Responsible management of scientific uncertainty comprises comprehensive analysis by the oncologist, of all relevant evidence-based and values-based considerations to identify the clinical judgments that they support. Such pragmatic epistemic humility facilitates managing uncertainties that result when clinical judgments fall short of the ideal of evidence-based medicine. ⁸

There are practical ways to increase tolerance of uncertainty and build resilience to avoid remaining in limbo. ⁹ Limbo, the first circle of hell in Dante's Divine Comedy, is a place where people have no hope yet live in longing. It is described as a gloomy, dimly lit wood; dark, deep, and foggy. What are first mistaken for cries of anguish are, in fact, sighs of sadness reflecting the agony of waiting. Reassurance is problematic when, given our current state of knowledge of cancer, the prospect of cure is always uncertain.

Philosophers have concluded that the best explanation of why medicine cannot reliably cure is that we still lack much understanding of the chemical, biological, and psychosocial facts that underlie health and disease. ¹⁰

Possibility and Probability of Cure

A diagnosis of cancer represents an existential threat that usually triggers an urge to eradicate the disease as quickly as possible. When detected early, while still localized, surgical or radiation therapy may be offered with curative intent with a reasonably high, but not certain, expectation that all malignant cells will be eradicated. However, if metastasis has occurred, the cure rate is low, consistent with the hypothesis that at least some cancer cells will survive virtually all current systemic treatments, even those involving multiple drugs. Therapy for solid tumors is rarely curative. ¹¹

Initial treatment of metastatic cancer can produce a partial or complete response, which is almost inevitably followed by disease progression. New drugs have generally increased survival in this cohort, although nearly all patients will eventually die of their disease. Evolution of resistance remains the fundamental barrier to cure and long-term disease control. Efforts to overcome resistance have had little clinical success, probably due to the multiplicity of the molecular mechanisms of resistance, the size and diversity of the heterogeneous cell population of the tumor(s), and the protected biological niches that such cells might occupy.

Novel strategies are being devised to increase the probability of disease control, or cure, by anticipating and steering the evolutionary dynamics of the inevitable acquired resistance. Application of evolutionary dynamics of extinction may maximize the probability of cure. ¹¹ Strategic sequencing of several effective, but non-curative, therapies could potentially be used to exploit the unique vulnerabilities of small and declining metastatic cell populations in an approach termed “extinction therapy.” This approach, directed at complete eradication of the minimal residual disease (MRD) state, is in direct contrast with current protocols that typically apply treatment agents at the maximum tolerated dose until there is unequivocal clinical evidence of progression. This standard treatment strategy is only changed with the emergence of clinically measurable disease due to a large emergent population of resistant cells.

The novel strategy of extinction therapy has been modeled on game theory. Cancer cells, similar to any other evolving population, can adapt only to current selection forces and although such cells have inherent plasticity, they are unable to anticipate the future, or to adapt to treatments to which they have yet to be exposed. The oncologist can exploit this vulnerability to stay ahead of the game by instituting tactical and timely serial changes in treatment regimens.

Tumor progression occurs by means of this selection of pre-existing subclones that are present early in cancer development. This Darwinian model of tumor evolution, and the highly plastic and adaptable pathways that signal cell proliferation or cell survival in cancer cells have led to the view that personalized cancer medicine has not led to substantial gains in survival or its quality. ¹²

A major hurdle in treating cancer continues to lie in our inability to overcome tumor heterogeneity at multiple levels. ¹³ To develop curative cancer chemotherapies in the future, we need to focus on the elimination of cancer cells that are the source of all cancer-related pathologies, including tumor cell stemness, plasticity, inflammatory tumor micro-environment, and evasion of host-immune surveillance. Thus, although precision cancer therapy with a molecular-targeted drug may be pathway precise, it is unlikely to be curative.

In an editorial titled “Redefining cancer and cure,” the Chief Editor of Nature Reviews Clinical Oncology wrote “as our understanding of cancer evolves, in parallel, we must evaluate how we define this disease in its simplest terms and what we mean by cure…. If no cancer cells remain after initial treatment, then this defines cure.” ¹⁴ Crucially, we need to define response in a patient-centric way and correlate that response with the biology of the tumor rather than using measurable end points, because they are convenient. We owe it to our patients to set the bar higher for end point definition so we can better correlate response with survival. ¹⁵

How, then, can we define response to inform the potential curative intent of treatment in an individual patient? Tumor cells have been shown to disseminate at the so-called in situ stage of cancer, well before detection of the primary tumor. ¹⁶ Although it has never been proved that disseminated tumor cells (DTCs) are the source of future metastases, when detected before or after adjuvant therapy, radiotherapy or surgical resection of the primary tumor, they constitute independent risk factors for relapse and death. ¹⁶ How do we shift the focus from treating metastasis to preventing metastasis when we currently do not have any drugs that specifically target DTCs or circulating tumor cells (CTCs)? In melanoma, prostate and breast cancers CTCs may enter into a quiescent state only to “awaken” after several years and form deadly metastases. Baseline detection of CTCs in both first-line and refractory metastatic breast cancer has proven prognostic significance. ¹⁷ Indeed, metastatic breast cancer continues to be considered incurable and is treated with palliative intent in spite of increased availability of Food and Drug Administration-approved therapeutic drugs designed to treat specific disease subtypes such as hormone receptor-positive disease. ¹⁸

A considerable percentage of patients with seemingly successful treatment of early stage cancer have occult micrometastases or MRD, which persist after initial therapy as a potential source of subsequent metastatic relapse at distant sites within 5 years. ¹⁹ The absence of evidence of MRD is not evidence of absence.

The War Against Cancer

Potential new molecular targeted precision cancer therapies are often heralded by military metaphors and curative intent. Recently, chimeric antigen receptor-T cell immunotherapy of leukemia at University College London was headlined in The Guardian as “War in the Blood review- love, hope, and the search for a cancer cure” ²⁰ However, within the context of the martial metaphor, patients fail treatment instead of treatment failing patients. ²¹ There have been recent pleas for an armistice in the combative language of cancer, with reference to carpet-bombing chemotherapy and smart bombs of targeted therapy, ²² and to mitigate the harmful impact of the rhetoric “war on cancer.” ²³

However, valuable lessons may be learned from the evolving theories of modern conventional warfare, in which individual battlefields, armies, and armaments are integrated into an overarching, holistic so-called battlespace that guides strategic war plans. This organizing principle might be applied to the development of an analogous battlespace plan for the war on cancer that integrates knowledge about the weapons, capabilities, strategies of expansive growth, resilience of adaptive resistance, and evasion of therapeutic attacks into what could become a new doctrine for the metaphorical war on cancer. ²⁴ If used judiciously, the battlespace concept may be of value in emphasizing the necessity to establish advanced combinations and temporal regimens of drugs that effectively target several classes of cellular soldier, so as to avoid adaptive resistance with use of tactical shifts among them, while limiting collateral tissue damage (toxicity). Moreover, it will be important to delineate potential variations in the abundance and characteristics of constituent cells in the tumor microenvironments of distinctive tissue and organ battlefields for a particular cancer. ²⁴

Practical application of these principles may be illustrated in treatment of advanced ovarian cancer, where conventional chemotherapy and surgery achieve a 20% survival at 12 years, which is deemed to be effective cure. Novel molecular targeted strategies can decrease the rates of recurrence and death but they do not improve the likelihood of cure. Applying battlespace holistic strategies to attempt to eliminate the ovarian cancer cells by using extensive surgical resection of all residual intra-abdominal disease visible to the surgeon's eye, followed by intraperitoneal chemotherapy has been reported to achieve cure in up to 50% (Ref. ²⁵ ). However, this cure of half the patients undergoing aggressive therapy with curative intent can only be determined retrospectively after a 12-year survival. Perhaps, ironically, definitive pronouncement of cure can only be made at the time of death. Such a view was presaged by Solon in 600 BC in respect of happiness: “Call no man happy before he dies, he is at best but fortunate.” In classical Greece, prognosis was the chief sign of medical acumen. After two-and-a-half millennia, the identification of women with and without microscopic disease is not possible, and the molecular features that discriminate between the prognosis of the two groups of women with advanced ovarian cancer remain unknown.

Prediction of Outcome in the Individual Patient

Given our current lack of reliable prognostic knowledge for each individual patient presenting with advanced ovarian cancer, aggressive therapy with the objective of eliminating residual disease to achieve a statistical cure outcome in half of them will be a matter of luck. The risk of recurrence may be discussed by oncologists in terms of probabilities, but from a medical philosophic standpoint, valid conclusions related to causal uncertainty can only be warranted when the underlying uncertainty is brought under control. ²⁶

An outcome that happens by “luck,” in fact, happens by natural causal mechanisms; it is only that we do not fully control these mechanisms. In medical practice, uncertainty is usually conceived metaphorically as the roll of the dice, or other forms of fixed gambling such as roulette, which transforms uncertainty into risk. But the primary problem with risk is the tacit assumption that life is not only a gamble; it is also a fair gamble, where you get what you deserve and you deserve what you get. ²⁶

A rational medical decision is one for which the physician first determines the probabilities, then calculates, evaluates, and decides what to do. However, the fair fixed gamble fails as a valid model because the preconditions are very rarely met in real life. We simply do not have the sort of control over nature that the model presupposes.

A philosophic perspective of the uncertainty connected to medical odds posits it to be of a different and more radical kind than the uncertainty connected to roulette. A more life-like dynamic gambling model, of rationally moving from uncertainty to action, is betting on horses. They are changeable and complex, and they interact with a changing and complex environment that has a dynamic time dimension. Things happen to them that are beyond the control of both them and us, and a winning outcome is subject to luck. Nevertheless, we are able to predict the performance of individual horses quite well, and medical risks can be determined by the same type of qualified guesswork. It is intuitively clear that the odds in a horse race are heuristic tools and not ultimate truths. ²⁶

The philosophic metaphor of gambling on horse races might not be entirely appropriate for application to care of cancer patients, but it does exemplify the nature of risk and the influence of chance, which have a substantial impact on medical decision making. Medical risk ratios in oncology management paradigms are probably right, but they may be wrong.

One should pay the risks sufficient heed, but make an individual choice on the basis of personal indications and act appropriately. In relation to clinical decision making on the basis of scant evidence, taking immunotherapy of advanced non-small-cell-lung cancer as an example, Passaro et al. concluded: “As for the individual patient in the clinic, the judgement should be made on a case-by-case basis as a shared decision between the physician and the patient until robust data are available.” ²⁷

Improving the Odds

The recent development of a systems biology-based deep phenotyping approach to personalized cancer care allows contemplation of individual targeted treatments by identification of aberrant biologically relevant molecular targets in tumor tissues toward which antibodies can be directed. This advent of appropriate immunotherapeutic regimens will be driven by new insights into immune cell dynamics in each patient. These therapies will require activity in the face of both intratumoral and intertumoral heterogeneity. Whole-genome sequencing of tumors and non-transformed germline tissues will enable the identification of driver mutations in tumors, as potential targets of therapeutic agents, and of genetic signatures in the tumor microenvironment, as potential immunotherapy targets. ²⁸ However, resistance will remain a problem and therapeutic regimens that incorporate various combinations of radiation, small molecules, antibodies, cell-based therapies, and surgical procedures, guided by a systemic understanding of the cancer-driven dynamics in each patient, will be required for success.

In the real world, such combination multimodality therapies of advanced metastatic cancer, although achieving variable success in prolonging survival, often at the cost of toxicity-impaired quality of life, have only on rare occasions been deemed curative. While awaiting the availability of novel efficacious and affordable complex treatments, and elucidation of the tumor biology mechanisms of metastasis and resistance that confound current cancer therapy, what strategy could potentially confer the cure of cancer in patients presenting in the immediate future?

Alpha Radionuclide Targeted Tumor Cell Kill

Isolated, individual tumor cells of advanced metastatic cancer could potentially be selectively targeted and killed by designer-ligand alpha particle-emitting radionuclide therapy. Given accurate delivery to the specified tumor cell, the physical properties of the 4–9 MeV energetic alpha particle provides a high linear energy transfer 60–230 keV/μm over a short path length,100 μm, resulting in a very high relative biological effectiveness. Just a few alpha particles traversing a tumor cell nucleus will kill the cell by self-irradiation, regardless of its oxygenation status. The efficient induction of complex DNA double-strand breaks makes cellular repair mechanisms ineffective. ²⁹

Clinical experience of alpha radionuclide targeted therapy of advanced metastatic castration-resistant prostate cancer (mCRPC) with Ac-225-prostate-specific membrane antigen (PSMA) showed that median overall survival (OS) was 18 months, with only minor toxicity. ³⁰ Proof-of-concept of the potential for cure was shown by the 5-year survival of a patient with very high tumor burden of mCRPC who regained his normal age-adjusted expectation of life. ³¹ This long-lasting complete remission was achieved in a chemo-naive patient and it highlights the importance of considering targeted tumoricidal alpha radionuclide therapy in an earlier phase of prostate cancer treatment rather than in a last-line salvage setting.

For Ac-225-PSMA treatment it appears that the number of lesions is not as important as their intrinsic sensitivity to radiation that governs response to therapy and OS. Thus, it may be important, when seeking to eradicate all tumor cells to pursue cure of advanced mCRPC, to choose prior therapies carefully so as to avoid potential evolutionary selection of intrinsic cancer stem cells that represent a small radio-resistant subclone, and which may become dominant with prior exposure to radiation, by either external beam or beta radionuclide Lu-177-PSMA treatment. ³⁰

In addition to direct cell kill by alpha irradiation, there are significant bystander effects and the immune system is stimulated to deliver an enhanced antitumor response. ²⁹ Significant changes in the tumor microenvironment have been observed to complement the potent and specific cytotoxicity due to Ac-225-ultra-small fluorescent core-shell silica nanoparticles targeting melanoma through alpha-melanocyte-stimulating hormone peptide moieties. ³²

Communicating the Chance of Cure

It is difficult to define a clear transition between the curative and palliative treatment phase of cancer. There is an unmet demand for conceptual clarity and transparent labeling of oncologic interventions with putative intent to cure, as against prolongation of life and/or palliative and supportive care, and the definition of these goals should be elaborated more thoroughly. ³³ Guidelines on approaching difficult communication tasks in oncology address completion of anticancer therapy given with curative intent, but they do not define cure. ³⁴

When oncologists discuss the possibility of discontinuing chemotherapy, they often have feelings of guilt and failure that they were unable to rescue the patient from impending death even with third- or fourth-line chemotherapy extending into the last months of life. ³⁵ Unfortunately, oncology clinicians often equate palliative care with end-of-life care. ^36,37 There is, in fact, considerable discordance between patients/caregivers and oncologists regarding cancer stage, treatment goal, and chance of cure. ³⁸ Physicians may provide explanations to the patients, but in a euphemistic and optimistic manner. The agreement of patient understanding with that of oncologists is lowest regarding their chance of cure. Many patients with incurable cancer inaccurately believe that chemotherapy may cure them. ³⁹ Addressing this disconnect, one clinician remarked “As a medical oncologist, I spend most of my time treating people with incurable cancers…I rarely say exactly what I mean: ‘It's only going to be a few months until you die’.” ⁴⁰

Oncology patients are looking for communication with their physician that allows them to feel guided, build trust, and sustain hope. ³⁴ However, oncologists are frequently unaware of the patient's personal preferences and quality of life and are unable to provide the patient information and emotional needs. ⁴¹

There is a common phenomenon of miscommunication in oncology in which information shared by the provider is believed to be complete or adequately explained but is, in fact, misinterpreted by patients. For example, after explaining clinical trial aims, which are seldom of individual therapeutic benefit to the research subject, patients may be left with the impression that “it may cure my cancer.” ⁴²

A recent celebration of “progress in cancer research, prevention and care” published in September 2020 in the New England Journal of Medicine mentioned cure only in relation to childhood cancers. It was remarked that targeted therapies produce spectacular short-term remissions of some difficult-to-treat cancers. However, long-term disease control is rare because of the emergence of drug resistance and tumor adaptation. ⁴³

The possibility of cure is an emerging survivorship issue and in the context of metastatic solid tumors, apart from testicular cancer and large cell lymphomas, oncologists have been hesitant to describe a patient as cured. In fact, two-thirds of Dana Faber Cancer Institute oncologists never uttered the word “cure.” ³ Many oncologists prefer to tell patients that they are “in remission” and that they hope it will last as long as possible. The parameters influencing the use of the word “cure” include a combination of elements linked to the type of cancer, the clinician's expertise, knowledge of the risks of late relapse, and fear of litigation. Hesitancy in describing a patient as being cured also results from a patient's perceptions of risk, which can be affected by subjectivity, including emotions and superstition. It may be an opportune time for oncologists to interrogate themselves on the definition of cure, because it does not seem to be unequivocal. Does a broadly accepted threshold for duration of remission exist, after which one can be sure that the patient is cured? Does cure imply that medical follow-up is no longer necessary? Is cure synonymous with an unaffected life expectancy? In reality, these questions have no clear answers among the oncology community. ⁴⁴

Immune-check point inhibitor immunotherapy, has, for some patients, modified the mental representation of the word “cancer,” because those with historically incurable disease can now sometimes have durable remissions without requiring maintenance therapy. ⁴⁵ In the context of immunotherapy, when shall oncologists feel authorized to tell their patients that they are cured? The difficulties surrounding the use of the term “cure” are linked with the novelty of the current situation and to the limited availability of hindsight. Discontinuation of a beneficial therapy in the context of a potentially fatal disease can put the patient and the treating physician on previously unknown ground, torn between the hope for cure and the fear of relapse.

Although curative-intent therapy of advanced metastatic solid tumor malignancy in adults may be an illusion, recent innovations in therapeutics are, in fact, prolonging life and giving rise to the prospect of long-term control of cancer. A recent study of long-term survivors explored the existential implications and the heightened sense of their own mortality awakened in these patients. Cancer alienated them from the world they knew and engendered a fundamental upheaval of self-perception, belief-system, and worldview: “One thing is to survive and be cured. It is an entirely different thing to reinvent oneself because who I used to be was gone. There is no turning back. You must rebuild a new understanding of what it means to be.” ⁴⁶ In this particular understanding of mortality, death becomes a life force full of potentiality and vitality. ⁴⁶

Hope Springs Eternal

Patients with advanced metastatic cancer with very limited options for cure today must live the remainder of their lives in a chronic state of uncertainty, receiving new therapies and combinations of treatments that did not exist just 5 years ago. How do they manage the tension between hope and reality in this age of discovery?

Novel genomics-based drugs work only in small percentages of patients and only for a limited time, during which they often cause serious and even fatal complications. Two oncologists, themselves suffering with long-term metastatic cancer, remarked that only 7% of similarly afflicted patients thought they could be cured when they could not, and they concluded that “we are not delusional - just hopeful.” ⁴⁷

Hope is based on a cognitive decision—a volition, to act as if the desired prospect of cure will become a reality or at least as if it has a good chance of being realized. This capacity to hope is a vital coping resource and, in itself, may improve outcomes of treatment. ⁴⁸

Doctors are reluctant to raise false hope but often fear that without the belief in a possibly effective treatment patients may fall into despair. However, a cancer patient who hoped that the first treatment would be successful may lose hope for success of that particular therapy without losing the hope that an effective treatment will be found. Since the belief that is part of hope is not a statement of fact, but a probability statement, from an epistemic point of view a particular hope cannot be true, it can only become true. Neither can hope be false, it can only turn out to be false. ⁴⁸

Doctors try to not only tell their patients the truth, but to also give them hope. They must strive to find the middle ground between “hope” and “truth.” Given this rapprochement, continuing to hope is both realistic and reasonable. Hope not only contributes substantially to the realization of personal goals in the remainder of life, but it also acts as a direct or secondary mediator of outcome of cancer treatment. ⁴⁹ In the real world, cancer patients hope for cure whatever the odds and whatever they are told.

Coda

Dying, which was once viewed as the natural and inevitable final act, a coda to our dance to the music of time, has now become medicalized. Exclusive focus on curative intent in therapy of advanced cancer carries an inherent risk of distorting an event of great cultural significance into the endpoint of untreatable disease, or worse, a failure to achieve a cure. The quality of death is a corollary of the quality of life and it is imperative that inappropriate aggressive therapy in pursuit of an unattainable “cure” not degrade the opportunity for fulfilment of personal life goals of the patient before they die. Our role as doctors is to cure sometimes, to relieve often, and to comfort always.