Philosophy of Cancer Theranostics

Introduction

Thinking about thinking is the essence of philosophy. When applied to the rationale and practice of radioligand targeted molecular therapy of cancer, philosophic reflection can provide critical insights prompted by our response to the questions what and why and when and how and where and who?

What is theranostics, why should we advocate its use in cancer treatment, when is the optimal time to treat, how should it be performed, where, and by whom?

These timely questions of theranostics are encompassed by the major fields of philosophy, metaphysics, moral philosophy and ethics. Although answers are not the purview of philosophic enquiry, the engendered in-depth reasoned analysis of theranostics may be expected to refine theory and practice and ultimately optimize cancer patient outcomes.

What?

Theranostics may be represented symbolically by an ancient Greek Doric temple, each of the three columns being respectively designated as “patient,” “molecule,” and “dose.” These essential supports of the theranostic edifice themselves require a firm foundation to be provided by the nuclear oncology physician, who manifests the Aristotelian philosophic medical tradition of phronesis: Practical wisdom with a moral compass.

Phronesis is the rational disposition to deliberate and to judge correctly. It encompasses the desirable physician attributes that permit the fusion of intellectual virtues, with truth as their end, and the moral virtues, with good as their end. Emotional intelligence must be accompanied by a state-of-the-art multifaceted theranostic knowledge base. In addition to cognizance of medical oncology and radiation physics dosimetry, precision radioligand targeted molecular therapy of cancer requires specific training that includes genomics, pharmacogenomics, and epigenomics, which all impact tumor receptor molecular expression, the microenvironment and immunoreactivity.

An understanding of radiobiology of cell death having regard to radiosensitivity and resistance is needed to determine the likelihood of tumor cell recovery, which may change with the evolution of new tumor clonal selection induced by initial cycles of radiation exposure, leading to increased uncertainty of treatment outcomes. Inevitably radioligand theranostics will be combined with newly developed cancer treatment modalities. To address current nonresponder rates of ∼30% for ¹⁷⁷Lu-PSMA in advanced prostate cancer, ongoing early phase clinical trials of ¹⁷⁷Lu-PSMA in combination with pembrolizumab anti-programmed death 1 inhibitor are promising. ¹ The complexity of such evolving chemo-immuno-radionuclide regimens will render continuing rigorous radiomolecular biological oncology training of nuclear physicians imperative.

Philosophic enquiry into the nature of molecular biology may be viewed as a metaphysical endeavor to uncover the underlying structure of reality as it relates to apparent known knowns, known unknowns, and unknown unknowns. Our present knowledge of cancer biology predominantly rests upon preclinical molecular studies, the independent experimental replication of which could not be achieved in the majority of studies published in scientific journals of record, such as Nature, Cell, and Science. ² A fundamental concern about replication is that it is difficult to assess whether reported findings are credible. Defining and understanding reproducibility, in addition to analysis of experimental methodology, require grappling with the psychology of expert inference and ethical and pragmatic judgments that demand further scientific, sociological, and moral enquiry. ³

What is the difference between magic and current theranostic treatment of the individual cancer patient? De facto, Magicians know what they are doing. ⁴

Although remaining skeptical of postulated causal mechanisms in radiomolecular biology, we do have recourse to the philosophic doctrine of pragmatism. Skeptics of classical antiquity, denying the possibility of achieving authentic knowledge of real truth, taught that we must make do with plausible information adequate for the needs of practice. In the realm of theranostics in cancer care, such plausible information can be reliably provided by real-world data in large unselected representative patient populations. Clinical outcomes for long periods of follow-up, documenting overall survival (OS), quality of life (QOL), and toxicity of novel radioligand regimens, constitute real-world evidence (RWE) that will permit a pragmatic clinically informed practical approach, applicable to the individual cancer patient anywhere in the world. Documentation of biological outcomes, related to radiation absorbed dose delivered, will help to overcome the current lack of radiobiological understanding and address unmet clinical needs. ⁵

Why?

Efficient control of metastatic cancer with prolonged survival and preservation of QOL may be consistently achieved by theranostic treatment of those tumor types that manifest a receptor targetable by a specific radioligand molecular therapy. Such cancers presently include thyroid cancer, prostate carcinoma, neuroendocrine neoplasm, and lymphoma, with potential additional applications in colorectal and breast cancer. ⁶

Reasons for the choice of theranostic treatment of cancer in the individual patient must be personally explained to the patient, and made clear to the referring oncologist, to achieve an optimal outcome in advanced disease. Theranostics is not to be viewed simply as a salvage therapy after failed chemotherapy. Intervention is not a synonym for care.

Theranostic cancer care is not curative. It is designed to achieve long-term control of progressive disease, prolonging survival and improving QOL by amelioration of pain and enhancement of well-being. In metastatic prostate cancer, ¹⁷⁷Lu-PSMA therapy can relieve skeletal pain and arrest tumor growth, often reducing the number of detectable metastases, without inducing the distressing side-effects associated with chronic androgen deprivation or chemotherapy.

In effect, theranostics of advanced prostate cancer may be viewed as a unique form of palliative treatment, where the key concept is that palliative care and therapies seeking to cure or prolong life are not mutually exclusive, nor do their philosophies conflict when they are integrated in a timely way. ⁷ However, urologists believe that patients, family members, doctors, and nurses view palliative care as giving up, and referrals are made when physicians identify no other options for the patient's treatment, or that the patient is very near the end of life. ⁷ Only 17% of oncologists refer their patients to palliative care at the time of diagnosis of metastatic disease. ⁸

How are we, as physicians, to understand that patients sometimes deny an accurate description of reality where they hear the facts (veritas), honestly recounted by their oncologist, but deny that they are true? The Greek term for truth, alathēia, meaning not hidden, emphasizes that truth is an opening or revelation of what is. For patients diagnosed with a life-limiting illness, accepting the medical facts (veritas) as existential truths (alathēia) that affect their very being, takes time, and multiple conversations. ⁹ Such time-consuming empathic communication is seldom practicable in the real world of medical oncology.

Among patients aged >70 years with advanced cancer, >40% believed that they had >5 years to live, and 60% believed their terminal cancer would go away and never return. ¹⁰ The failure to reach mutual understanding of the prospects of success in treatment results in oncologists prescribing toxic chemotherapy in more than half of their end-stage cancer patients within 6 months of their death. ¹¹ In terms of moral philosophy, it may be questioned why doctors continue to provide high intensity care for terminally ill patients, but personally forgo such care for themselves at the end of life. ¹²

Theranostic cancer care may be anticipated to be most efficacious in patients in relatively early stages of advanced cancer. It is the responsibility of the nuclear physician to address misconceptions of survival and QOL outcomes, in both patients with metastatic cancer, and their medical oncologists. Theranostic nuclear physicians have a duty to clearly explain the realistic expectations of targeted radiomolecular cancer care to reach mutual understanding of the achievable outcomes of control of progressive disease, enhanced QOL, and prolonged survival without significant toxicity.

Frontline androgen-deprivation therapy can, according to long-term surviving patients, cause “great misery and suffering… Mainstream oncology is slowly recognizing that its ability to keep men with advanced prostate cancer alive has outstripped its ability to manage the often soul-crushing side effects of treatment.” ¹³ Such chronic impairment of QOL is likely to be exacerbated by subsequent chemotherapy that may cause neurotoxicity and “chemo-brain” cognitive dysfunction in up to 75% of patients. ^14,15

Reassurance of the theranostic patient that they will not experience chronic poisoning of body and soul will do much to foster psychological coping strategies, such as “cognitive flexibility,” ¹⁶ which may promote adaptation to cancer life circumstances, and even allow a degree of flourishing. ¹⁷

In the context of clinical psycho-oncology, the notion of “soul” emphasizes “being human”, through philosophic reflection and contemplation of the arts, humanities, and spirituality, all of which are linked to phronesis and the virtues of practical wisdom. ¹⁸ These virtues are ideally manifest in the theranostic nuclear physician. “Soul” has assumed a pragmatic meaning, rather than only a religious or spiritual meaning, linking it to our capacity to imagine, create, lament, and celebrate, and most importantly to discover a patient's own unique wisdom. ¹⁸

From the viewpoint of a patient; “I would like a doctor who is not only a talented physician but a bit of a metaphysician too - someone who can treat body and soul. There's a physical self who is ill and there's a metaphysical self who is ill…To get to my body, my doctor has to get to my character. He has to go through my soul.” ¹⁹ We are each driven to create a unique life, with direction and meaning, and growth and transformation, to become an effective and useful member of a larger culture or society in a world that we imbue with meaning.

The process of (re)creating yourself when plunged into turmoil by a terminal cancer diagnosis, at its essence, involves the creation of the attitude you take toward life: life, love, and suffering. Creating your attitude is essentially creating your soul—from the Greek philosophical perspective, your mind and spirit. ²⁰ Epicurus, through empirical reasoning, concluded that the human organism is simply a compilation of atoms, and our death is marked by the entire dissipation of our existence consequent upon the disarrangement of those atoms. Plato, however, embraced dialectical reasoning, detached from empirical observation, which leads to a firmly held belief in an otherworldly existence, such as a world of forms, whence the soul arises and to which it will return after bodily death. In Greek philosophy, whereas for Epicurus death is nothing to us, for Plato death is the transformative portal to another world beyond the material realm. ²¹

It is of profound import for the caring oncology physician to be aware of the patient's own concept of death, and their personal belief in a soulful essence, which they themselves may be unable to articulate. The advent of life-threatening cancer indeed might well be the first time that the patient has been confronted by their existential core; “Know thyself,” the Ancient Greek injunction inscribed in the Temple of Apollo at Delphi.

When?

Theranostic management of metastatic cancer should be contemplated at the time of diagnosis by PET/CT when tumor receptor avidity is first demonstrated. In metastatic castrate-resistant prostate cancer treated with ¹⁷⁷Lu-PSMA OS was significantly better in chemotherapy-naive patients; being 27.1 months versus 10.7 months in patients who had received prior taxanes. ²² To facilitate early and appropriate referral for radioligand molecular cancer therapy, the diagnostic test referral/order for PET/CT imaging should be reformulated as a request for nuclear physician consultation, rather than being regarded by the oncologist simply as an anonymous laboratory test result from a radiologist, invisible in a dark reporting room. Such a paradigm shift would permit immediate feedback and expert interpretation of the potential for effective radiotheranostic tumor targeting. Authoritative discussion with the individual patient, and their referring oncologist, could then promote optimal personalized cancer care.

Metamorphosis of the nuclear medicine diagnostician into a theranostic nuclear physician oncologist, consulting with medical oncology colleagues is devoutly to be wished. Such collegiate consultation would minimize the adverse effects of the current trend toward standardized proforma image reporting by diagnostic nuclear radiologists conforming to the implacable demands of artificial intelligence (AI) algorithms, imposed by bureaucratic exigencies of evolving institutional cancer management guidelines.

The European Association of Nuclear Medicine (EANM) recognizes that there is a long road ahead before the potential of AI in nuclear medicine is realized in a manner acceptable to both health care professionals and patients. ²³ AI is amoral and has no intrinsic empathy, compassion, responsibility, or accountability. Philosophers regard theranostics as a graspable “known unknown,” whereas the “Doctor Ex Machina” of AI in health care possesses the potential of being an “unknown unknown” since it is not even possible to define a spectrum of consequences. ²⁴ Artificial superintelligence is multifaceted and, therefore, is potentially capable of mobilizing a diversity of resources to achieve objectives that are potentially incomprehensible to humans, let alone controllable. ²⁵

How?

How is “precision radiomolecular cancer therapy” to be approached? “Precise” is defined in terms of “the particular, the identical, the exact.” ²⁶ Given the multifactorial uncertainties of the molecular radiobiology of cancer, it is self-evident that such precision cannot be strictly ascribed to the clinical practice of theranostics. Nevertheless, a major step toward rigorous theranostic cancer care would be to prescribe, deliver, and verify the radiation absorbed dose in each patient, measured and documented in Gray, as is routine clinical practice in conventional external beam radiation oncology.

Individual dosimetry is currently mandated by EU regulation. ²⁷ The EC Directive 2013/59/Euratom article 56 states: “For all medical exposure for radiotherapeutic purposes, exposures of target volumes shall be individually planned and their delivery appropriately verified.” In clinical practice this appearance that dosimetry is to be performed in all patients is an illusion. The prescription of a fixed administered activity, measured in GBq, cannot be reliably correlated with the biologically effective dose (BED) measured in Gy. Radiation absorbed dose to NET treated with ¹⁷⁷Lu-DOTATATE varies between 0.1 and 32 Gy/GBq. ²⁸ Standard fixed administration of 7.4 GBq shows wide variation of tumor dose between 2 and 77 Gy per cycle. ²⁹

Although tumor uptake and retention of targeted radioligand is highly variable, the radiation absorbed dose to critical normal organs is more uniform and may be used to define the maximal tolerated administered activity to ensure optimal theranostic treatment with minimal toxicity. Survival probability has been shown to be enhanced by increasing critical organ renal radiation absorbed dose from 25 Gy to >29 Gy in NET patients treated with ¹⁷⁷Lu-DOTATATE on an individual measured dosimetry basis. ³⁰ Personalized quantitative SPECT/CT dosimetry of peptide receptor radionuclide therapy could potentially improve efficacy by optimizing tumor BED and limiting radiotoxicity.

The practical accuracy of such dosimetric methodology is claimed to currently approach 20% with respect to accuracy of SPECT quantitation. ³¹ However, the actual radiation absorbed tumor dose also depends upon other parameters, such as area under the time/activity curve, and our inability to reliably define target lesions that are often small with heterogeneous uptake, which may confound accurate delineation of BED. The advent of commercially available software for semiautomated hybrid 3D dosimetry methodology offers a pragmatic approach to routine calculation of individual radiation absorbed dose, which is potentially applicable to all theranostic practices throughout the world. ³²

The relatively high nonresponder rate of metastatic prostate cancer to fixed administered activities of ¹⁷⁷Lu-PSMA radioligands may be addressed by prospective quantitative SPECT tracer studies for pretherapy estimation of BED to both critical normal organs and tumors. ³³ Prospective dosimetry cannot be accurately estimated on diagnostic PET/CT studies of ⁶⁸Ga-DOTATATE or ⁶⁸Ga-PSMA due to the relatively short half-life of 68 min, which precludes performance of the necessary serial uptake studies to evaluate tumor retention. The advent of ⁶⁴Cu-SARTATE PET/CT has the potential, given the 12.7 h half-life, to allow serial quantitative imaging for measurement of tumor and critical organ uptake for prospective extrapolation to ⁶⁷Cu-SARTATE therapy of NET. ³⁴

Pretreatment 3D dosimetry of ⁶⁴Cu/⁶⁷Cu-MeCOSar is currently performed in patients with inoperable meningioma, and up to five to eight cycles of therapy may be given before a radiation absorbed dose limit of 30 Gy to kidneys or 2 Gy to bone marrow is reached. ³⁵ Copper-67-octreotate appears to be a safe alternative theranostic agent for somatostatin-expressing tumors, and the capacity for pretherapeutic ⁶⁴Cu-octreotate PET dosimetry will be particularly valuable when treating pediatric patients where no reliable dose-scaling for age and size exists.

Routine performance of prospective tracer critical organ dosimetry by quantitative whole-body validated gamma imaging ³⁶ has been performed in every patient undergoing ¹³¹I-rituximab radioimmunotherapy (RIT) of non-Hodgkin lymphoma (NHL) in our institution for the past 20 years. A prescribed measured whole body dose of 0.75 Gy, predicated upon a red marrow critical organ dose limit of 2 Gy, resulted in administered therapeutic activities that ranged between 1.5 and 6.0 GBq. Long-term follow-up of first-line single dose ¹³¹I-rituximab RIT of aggressive follicular NHL for 10 years demonstrated OS 80%. Less than 20% of patients had required any other treatment. No clinical toxicity was observed, and no hospital admission was required. ³⁷

The efficiency of theranostic cancer care is best evaluated by actual clinical practice data, which documents OS and patient-reported outcomes of QOL. Long-term prospective follow-up of each patient until the defined endpoint of date of death will be required to establish the rightful place of theranostic management in routine oncology clinical care. These theranostic desiderata echo the stated aim of a past president of ASCO: “Caring for every patient, learning from every patient.” ³⁸ The personal clinical experience of the nuclear physician oncologist may then be applied directly to continually improve routine practice in a real-world population of patients.

Evaluation of such RWE should be contrasted with randomized controlled trials (RCTs) in highly selected populations of research subjects, followed short-term, just long enough to obtain surrogate statistical data on putative efficacy, such as objective response rate or progression-free survival (PFS), which are unreliable predictors of OS. These Pharma-generated statistics then become the foundation of evidence-based medicine (EBM), which customarily informs therapeutic decisions of multidisciplinary tumor boards even though the data set cannot be validly applied to individual patient care. In fact, the supposed RCT truths upon which EBM is based are not self-evident, being based almost exclusively on evidence derived from proprietary Pharma clinical trials supporting their approval.

Less than 10% of the clinical trial data upon which FDA approval of Nivolumab, Pembrolizumab, and Pomalidomide, which, taken together, in 2021 generated >$25 billion profit for Pharma, are available for independent review. ^39,40 The unreliability of Pharma RCT evidence of efficacy of prediction of survival benefit on the basis of surrogate endpoints, such as PFS, is illustrated by the independent audit of 10 cancer drugs approved by the FDA on accelerated approval pathways, which upon subsequent re-evaluation were confirmed to lack clinical OS benefit. ⁴¹ Indeed, “the oncology community has historically done a poor job of distinguishing statistical significance from clinical significance.” ⁴²

Where?

Therapeutic radioligand administration is logistically relatively simple and may be practically performed by appropriately trained personnel in any nuclear medicine facility with SPECT/CT and access to PET/CT imaging. A joint EANM SNMMI IAEA Enabling Guide how to set up a theranostics center ⁴³ is an excellent reference, but the recommendations and requirements for relatively complex logistics should not deter nuclear physicians in the wider world from developing simpler protocols appropriate to their local resources and patient needs.

No matter where a clinical theranostic practice is to be developed, its establishment and subsequent evolution will be facilitated by recourse to a network of mentors and experienced partners, such as may be accessed through the International Centers for Precision Oncology (ICPO), the World Association for Radiopharmaceutical and Molecular Therapy (WARMTH) and the European School of Multimodality Imaging and Therapy (ESMIT) to ensure adequate ongoing training and education in the fundamental sciences that underpin molecular radioligand therapy.

The imperative is to treat all patients throughout the global nuclear oncology community according to safe effective harmonized theranostic protocols, with uniform reporting of clinical outcomes, to establish definitive authoritative evidence of efficiency acceptable to oncologists, patients, and regulatory agencies.

The place where theranostic treatment is administered may be influenced by the patient's philosophic value perception in regard to cost-benefit. Financial toxicity is highest in the United States where Novartis has fixed the price of ¹⁷⁷Lu-PSMA-617 @ $42,500 per cycle ^44,45 Thus a 6-cycle course will cost patients in America a quarter of a million dollars for the radioligand alone, to which must be added administration and PET/CT costs. In Australia the overall cost to patients is $7,500 per cycle, and government subsidy under the Medical Benefits Scheme is currently under consideration. In India the cost-recovery price per cycle is $300. ⁴⁶

The vagaries of national radiation regulatory agencies, especially in European jurisdictions that require hospital in-patient confinement of treated patients in shielded rooms for up to 5 d, constrains access to theranostics to only a few specialized centers. In contrast, in those countries such as Australia, where discharge of patients after radionuclide therapy is permitted when the measured radiation exposure falls <25 μSv/h @ 1m, virtually all patients treated with ¹⁷⁷Lu-DOTATATE or ¹⁷⁷Lu-PSMA are allowed home within 5 h of administration of therapy.

No hospital admission is required, the patient simply being treated in a reclining chair in the nuclear medicine facility. Follow-up quantitative dosimetric imaging is then performed at appropriate intervals on an outpatient basis. Several patients may be treated at the same time, in the same room, which promotes doctor–patient and patient–patient communication, without the time constraints of formal consultations, and engenders confidence in the whole theranostic process through sharing of experiences. This positivity is enhanced during repeated cycles, and recurrent patient encounters with fellow patients and their nuclear oncologist, who has ample scope, and the time, to practice meaningful phronesis.

Who?

The practice of theranostics requires a highly skilled professional team comprising radiochemist, physicist, and specialized nurse under the direction of the nuclear physician oncologist, who is directly and personally responsible for selection and treatment and follow-up of each individual patient. Radiologists and medical oncologists require additional rigorous specialty training in nuclear medicine theranostics before embarking upon tumor-targeted radiomolecular therapy. That such formal instruction in the theory and practice of theranostics is imperative is exemplified by the apparent ignorance of theranostic principles manifested by an authoritative “international multidisciplinary group of prostate cancer experts.” ⁴⁷

They conclude, in their publication April 2022 in the Journal of Clinical Oncology, that their “shared recommendation is that there is little utility currently for the routine use of PSMA-PET in patients with detectable metastases on conventional imaging (CIM) [^99mTc-bone scan and CT scan] and recommendations regarding therapy should be based on CIM findings” ⁴⁷ Quite apart from this recommendation being “akin to managing lung cancer using chest X-rays instead of computed tomography,” ⁴⁸ it violates the fundamental tenet of theranostics: “We see what we treat and we treat what we see”. Treating a patient without prior assessment of the targeted tumor molecular receptor expression on PET/CT is, metaphorically, attempting to practice precision theranostics blindfold.

Having chosen to offer a particular radioligand therapy, the nuclear physician requires the informed consent of the patient. The concept of consentio, to feel together, to agree, has recently been refined by advocating attainment of moral consensus, which is tolerant and respectful of values of pluralism and patient autonomy. ⁴⁹ It is the duty of the nuclear physician oncologist to personally place the proposed cancer treatment within the context of the individual patient's own concepts of meaning of their life and their ethical values, to achieve a morally correct decision with, and for, them. Reaching consensus in cancer care thereby achieving truly informed consent requires an inclusive and noncoercive reflective dialogue, where all participants have an equal opportunity to contribute, and each is willing to accept accountability to reach, with guidance from the responsible physician, mutual understanding.

In the real world of medical oncology, the opportunity for in-depth discussion with patients and their carers rarely occurs. Patients complain that “the lack of opportunity for a more wide-ranging conversation about treatment options, how I'm holding up emotionally and strategies to mitigate the life-sapping side effects of treatment just feels wrong…More than anything I'd like a bit more evidence that he cares.” ¹³

Conclusions

We can do better. Philosophic reflection upon our practice of theranostics has the potential to promote our transformation from diagnostic nuclear imaging radiologists into therapeutic nuclear physician oncologists, who are willing to take direct responsibility for individual patient care.

Coupling state-of-the-art technical excellence with the emotional intelligence of phronesis will act to ensure moral and ethical theranostic practice as well as optimal clinical outcomes for each of our patients, with due regard for both the quality of their life and prolonged survival.