Theranostic Innovation by Humane N-of-One Cancer Care in Real-World Patients

Introduction

The “Common Sense Oncology” movement was established in 2023 to address the realization that “Oncology needs a recalibrated approach that is more patient centred and prioritises patients' needs with treatments that improve survival and quality of life which are outcomes that matter … Often the goal of improving and lengthening the lives of patients and that of making a profit for commercial organisations are not concordant.” ¹

Pharma-funded randomized controlled trials (RCTs) are designed to achieve regulatory approval or commercial advantage. Recruitment criteria are so selective that patients in minority groups, or those whose organ function or performance status are impaired, constitute an evidence-free zone for many approved cancer drugs.

The primary objective of the oncology physician, ideally, is to provide the best possible personal care of each individual cancer patient according to the Aristotelian tradition of phronesis, which is the essence of patient-centered treatment. ² The real world, beyond the restrictive boundaries of the nongeneralizable RCT evidence base, comprises a very significant number of cancer patients who do not satisfy eligibility criteria for novel chemoimmunotherapy agents, or who cannot afford them even if offered access, or who do not wish to subject themselves to the consequent protean debilitating side-effects.

Compassionate, real-world N-of-One theranostic studies can potentially offer practical, effective, affordable, humane theranostic care of cancer patients considered to be preterminal. Assiduous follow-up of these individual patients, treated on compassionate use protocols, may provide real-world evidence (RWE) of effectiveness, which could then be extrapolated to early-phase physician-sponsored studies to explore the potential for routine clinical theranostic application to palliate advanced malignancy.

RWE: N-of-One Studies Versus RCTs

The preamble to the Joint European Association of Nuclear Medicine (EANM)/Society of Nuclear Medicine and Molecular Imaging procedure guideline for ¹⁷⁷Lu-PSMA radioligand therapy 2023³ states that: “The ultimate judgement regarding the propriety of any specific procedure or course of action must be made by the physician … a conscientious practitioner may responsibly adopt a course of action different from that set forth in the guidelines when, in the reasonable judgement of the practitioner, such a course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to the publication of the guidelines.”

Innovation in theranostics of cancer is the prerogative, and the responsibility, of nuclear physicians who care for patients. The advances made in radionuclide treatment of malignancy have, almost exclusively, been made by individual doctors devising novel theranostic approaches to particular cancers in patients under their care, usually on the basis of compassionate usage. Such personal studies have led to Phase 1/2 clinical trials, sponsored by the investigators in academic university hospitals. ⁴ Only after the effectiveness of these novel radioligands became clearly apparent in these real-world clinical studies, did Pharma become involved to perform the Phase 3 RCTs demanded by regulatory agencies for approval. Pharma then marketed the radiopharmaceutical at an arbitrary, inflated, price predicated upon an envisaged profitable return.

For example, the wholesale price set by Novartis for ¹⁷⁷Lu-octreotate marketed as Lutathera in the United States is US$53,200 per cycle ⁵ to which must be added hospital and nuclear medicine specialist costs. In contrast, the total cost per cycle of ¹⁷⁷Lu-octeotate therapy in Australia in private clinics is around US$4000, and Australian resident patients are eligible to be treated gratis in public university teaching hospitals. Even so, Novartis is reportedly now seeking to sell their AAA radiopharmaceuticals theranostics assets as part of a Pharma “industry-wide push to cast off low growth business lines.” ⁶

Randomized clinical trials conducted by Pharma treat the patient as a means to an end of regulatory and marketing drug approval. In contrast, physicians conducting early-phase clinical studies treat the patient as the end in themselves, and in doing so satisfy basic Kantian ethical principles. ⁷

While it has been generally acknowledged that, for regulatory approval, RCTs are the gold standard for drug evaluation, a recent review in Nature on July 20, 2023, asked, “How many clinical trials can't be trusted?” In fact, at least one quarter of RCTs might be problematic or fake. ⁸ A recent review of RCTs in an advanced/metastatic cancer setting, which reported overall survival (OS) as a secondary endpoint, there was a substantial variation in methodology for OS reporting and many trials lacked, or deviated from, the prespecified plan for characterization of OS. ⁹

Many drugs have been approved and marketed on the basis of significant differences in progression-free survival (PFS) between the arms of an RCT, which, with longer follow-up, failed to report a significant improvement in OS. Blanket acceptance of PFS as a primary endpoint for full registration of new drugs in cancer has led to clinical use of therapies that produce no significant improvement in OS or quality of life (QOL). ¹⁰

In practice, there is no agreed definition of what constitutes the value of any particular anticancer drug since the perception of effectiveness will differ among patients, clinicians, regulators, payers, and Pharma industry. ¹¹ Recent advances in molecular biology and genomics have revolutionized precision oncology, and the exponential development of novel targeted anticancer agents has overwhelmed the traditional RCT processes leading to regulatory approval. Concomitant evolution of molecular imaging and artificial intelligence processing and quantitation of imaging and histopathological and omics data has now allowed contemplation of specific molecular receptor targeting of both primary and metastatic tumors in any given cancer patient. ¹²

Patients with advanced cancer harbor a median of five unique oncogenic alterations and unique N-of-One molecular profiles, which have been characterized as “malignant snowflakes.” ¹³ Even when individualized combination chemoimmunotherapies specifically target demonstrable biomarkers, when multiple co-driver alterations exist, it is likely that patients will exhibit primary or secondary resistance to such therapeutic strategies.

RCTs, on the whole, have failed to inform drug selection for an individual patient requiring palliative care. ¹⁴

An advantage of theranostics is that tumor molecule targeted radioligands have the potential to irradiate heterogeneous cancer cell populations provided only that the major proportion of cells express the target receptor demonstrated on pretreatment theranostic imaging studies. “We see what we treat and we treat what we see.” Pretherapy positron emission tomography/computed tomography (PET/CT) quantitative molecular radioligand imaging studies, in all patients with advanced cancer in whom theranostic palliative care is contemplated, directly define the affinity of the tumor target by measuring standardised uptake value and are a prerequisite for successful radionuclide therapy with β-emitters such as Lutetium-177. In addition, post-therapy SPECT/CT is critical because tumor retention is also a prerequisite for ensuring adequate radiation absorbed dose delivery for efficacy. ⁴ These simple, routine quantitative imaging procedures will prevent futile theranostic management of individual patients and help to mitigate the engendering of so-called false hope of clinical benefit, before commitment to a course of radioligand therapy.

It is a misconception that single-case therapies are “qualitative” or “descriptive” case studies. ¹⁵ Theranostic N-of-One quantitative studies are designed prospectively and collect data from an individual patient repeatedly and systematically over time. Collection and collation of real-world data (RWD) by nuclear physicians practicing personalized molecular radioligand molecular theranostics with novel agents can be envisaged to eventually constitute RWE of effectiveness of innovative approaches to treatment of advanced metastatic cancers expressing defined accessible and actionable tumor targets. Coordinated N-of-One trials have the potential to radically change the way in which evidence-based cancer care is practiced and to identify prospectively future patients likely to benefit. ¹⁴

An editorial in the Journal of Nuclear Medicine on November 9, 2023, concluded that: “To catapult nuclear medicine forward in this new era of precision oncology, we need to adapt. Hybrid approaches learned from n = 1 approaches and oncologic phase 1 approaches are needed to propel our field forward.” ⁴ Indeed, much of the contemporary early-phase theranostic development can be attributed to small biotechs in partnership with innovative physicians in a collaboration, which fosters design, synthesis, and translation of radioligand molecules into the clinic. ¹⁶

N-of-One cases can demonstrate the feasibility of designing and administering truly personalized theranostics and providing proof of effectiveness in each individual cancer patient in real-world clinical practice. It should, however, be acknowledged that not all patients respond to theranostic palliation, even when PET/CT screening and post-therapy imaging have demonstrated favorable tumor radioligand uptake and retention likely to deliver a tumoricidal dose. Other limitations to extrapolation of N-of-One studies include patient selection bias, absence of rigorous dosimetry data on radiation absorbed dose to tumor and critical normal organs, and the unquantifiable effects of prior immune-chemotherapies and concomitant combination treatments. Nevertheless, proof-of-principle can be demonstrated in novel N-of-One studies performed with the prime objective of pain relief, enhancement of QOL, and prolonged survival in the compassionate palliative care of individual cancer patients in the clinic.

Historic Survey and Current Status

The Way Forward

Technology of radionuclide production for theranostics is improving exponentially, and the availability of actinium-225, ⁴⁹ terbium-161, ⁵² and lead-212⁵⁹ is likely to improve in the near future.

Revision of unduly restrictive EU pharmaceutical regulatory legislation, in respect of radioligands, is now under active negotiation with EANM and regulatory authorities, ⁶⁰ which is also anticipated to facilitate radioligand approvals. However, there remain two major regulatory impediments to routine clinical practice of theranostics of cancer, which are the subject of deafening silence.

The Elephant in the Room

In fact, in the Northern Hemisphere, there are two elephants barring timely clinical application of humane, effective, theranostic palliative care, both attributable to regulatory agency intransigence. In the United States, Canada, and Japan, the imprimatur of the FDA is withheld until Pharma Phase 3 RCT proof of efficacy of each and every theranostic agent is demonstrated, often many years after RWE of multicenter Phase 2 studies in Europe and Australia have shown incontrovertible evidence of effectiveness with negligible toxicity. ^36,43

In Europe, draconian national regulators demand incarceration of theranostic patients for up to 5 days in shielded hospital radiation isolation units after the administration of standard therapeutic activities, which are routinely given to patients in Australia on an outpatient basis. Measured radiation exposure in Australian patients 3–5 h after the administration of standard therapeutic activities of ¹⁷⁷Lu-octreotate or ¹⁷⁷Lu-PSMA is below the IAEA exposure limit of 25 μSv/h at 1m, ^{61 –63} and all treated patients go home the same day.

The American Elephant differs in principle from the European Elephant; however, the existence of each in one jurisdiction but not in the other militates against the rational legitimacy of both. It is past time that the presence of these elephants were to be acknowledged so that they may be escorted from the room to provide affordable, accessible, practical, humane theranostic cancer care in the Northern Hemisphere and attain fulfillment of the current routine expectation of cancer patients treated in the Southern Hemisphere.

Salvage Versus Salvation

Salvage therapy of preterminal cancer, characterized by aggressive chemotherapy prescribed in the majority of patients within 6 months of their death, has been popularly perceived as “poisoning patients into the grave.” ⁶⁴ The use of systemic treatment at the end of life is, by definition, futile and is highly correlated with emergency department, hospital and intensive care unit utilization, late transition to hospice, death in the acute care setting, and higher costs, leading to distress among patients and caregivers. ⁶⁵ Almost a third of end-of-life patients receive systemic chemotherapy within 30 days of death.

A recent editorial, April 10, 2023, in the Journal of Clinical Oncology remarks “a shift from cytotoxic chemotherapies to the increasing use of checkpoint inhibitors at the end of life-a worrisome development in light of evidence that many if not most hospitalized patients who receive checkpoint inhibitors die shortly thereafter (i.e., roughly 40% and 80% of inpatients died within 30 days and 180 days of checkpoint inhibitor administration, respectively, thus enduring the burdens it imposes without realizing much, if any, of its benefits. Widespread enthusiasm for the benefit of chemoimmunotherapy in many newly diagnosed patients appears to be misplaced and potentially harmful in those near the end of life. The shift to new modalities of systemic anticancer therapies at the end of life does not appear poised to improve quality of life or quality of death.” ⁶⁶

Theranostic palliative care offers a unique opportunity to localize and target receptor molecules in specific cancers. The tumor uptake is demonstrated before instituting salvation therapy, thereby maximizing the chance of individual clinical survival benefit with enhanced QOL while eschewing toxic gambling in patients suffering late-stage malignancy.

Conclusions

Accurate documentation of RWD obtained from serial N-of-One studies of novel, theranostic, compassionate, patient use applications in patients unable to access effective standard therapy will provide cumulative RWE of effectiveness, which may then be corroborated in physician-sponsored early-phase clinical trials. From such small beginnings, humane innovative theranostics may become translated into salvation outcomes of prolonged survival and relief of suffering in patients with end-stage cancer, worldwide.

N-of-One case histories offer proof-of-concept of the effectiveness of molecular tumor-targeted α- and β-radioligands for palliation of advanced metastatic cancer in real-world patients treated by simple administration of innovative theranostics, without consequent clinical toxicity. Rather than “Salvage Therapy,” this theranostic management of cancers considered to be preterminal may be more appropriately termed “Salvation Therapy,” which treats both body and soul and enhances QOL while meaningfully prolonging survival at home with family and friends.