Rationale, results and roadblocks of combining external beam radiation therapy with radionuclide therapies

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Exclusive Commentary by Professor Nat Lenzo, Professor Nat Lenzo, Nuclear Medicine Physician and Medical Director of Theranostics at GenesisCare and Nadia Falzone, PhD, Clinical Physicist, GenesisCare

Theranostics – also known as targeted radionuclide therapy or molecular radiotherapy (MRT), provides a new approach on how we target and treat cancers. This approach moves away from defining cancers in terms of their location, such as lung cancer or stomach cancer, but rather focuses on what molecular biomarkers can be targeted in a specific cancer to deposit a radioactive treatment payload. So far MRT has shown great utility in the treatment of thyroid cancer, carcinoid tumours and advanced prostate cancer but this approach is possible in all tumour types.

More research is required to evaluate the effectiveness of MRT in other cancers and additionally, how to improve the efficacy of this treatment modality, likely through the combination with more standard approaches such as chemotherapy, immunotherapy and external beam radiotherapy.

External beam radiation therapy (EBRT) has been a mainstay of cancer medicine for over a century. Surprisingly, there has been very little research into the combined use of Theranostics and EBRT with few examples of their combination in clinical protocols.

In recognition of the current gap in research, GenesisCare and the Oxford Institute of Radiation Oncology, University of Oxford in the United Kingdom reviewed current data to put forward the case for combining MRT with EBRT in their paper published in the Journal for Clinical Oncology: Combining External Beam Radiation and Radionuclide Therapies: Rationale, Radiobiology, Results and Roadblocks.

 

Advantages of combined therapy

The combination of focally and locally administered EBRT together with the systemic but targeted radionuclide therapy or molecular radiotherapy, opens up a new and potentially very effective approach in the management of aggressive cancers. It does not preclude the use of other potentiating agents, such as immunotherapy, and has a number of theoretical benefits – including better cancer control with less administered dose and less early and delayed side effects.

The concept of ‘spacial cooperation’ was first used to describe the advantages of combining EBRT with chemotherapy: EBRT can debulk or effectively kill most of the primary tumour, while co-administered systemic therapy contributes to the control of the primary cancer and eliminates secondary metastases. This same principle can be applied to combining EBRT and MRT.

Another advantage of combining MRT and EBRT is that the organs at risk of toxic effects differ for each treatment. Modern advancements in surface guided radiation therapy have allowed radiation oncologists and therapists to directly target the tumour, while minimising exposure to surrounding healthy tissue. In Theranostics, radionuclides deposit radiation at the targeted tumour and the dose rapidly falls off with distance from the tumour thus preserving healthy surrounding tissues.

In addition to spatial co-operation and non-overlapping toxicity profiles, combining EBRT and MRT may enhance tumour response to treatment from differing methods of action.  One example is their combined effect on the immune system. Reports indicate that the two treatments cause changes to the immune system which may be harnessed for therapeutic gain.

Finally, Theranostic radiopharmaceuticals offer both treatment and imaging capabilities, in combined regimens, radiopharmaceuticals could also be utilised to identify tumour biology prior to radiation therapy.

While there has been very limited research into combining external beam radiation therapy with Theranostics, some retrospective data analysis does exist, describing patients who received both radiation therapy and Theranostics, however not as a pre-planned combined protocol.

A phase II clinical trial currently underway, the RAVENS trial, focusses on patients with prostate cancer and three or fewer metastases who are randomised to stereotactic body ablative radiation therapy alone, or combined radiation therapy with a radionuclide therapy, radium-233.

Sustained response to Lutetium-177 PSMA therapy has also been demonstrated in relatively small volume nodal disease in metastatic prostate cancer, across hormone-sensitive and castrate-resistant settings. The addition of Stereotactic body radiation therapy (SBRT) or volumetric modulated arc therapy for persistent or radioligand-resistant disease may prolong treatment response by eradicating more resistant tumours.

Despite the advantages outlined above, there are currently no international protocols or guidelines around the combination of EBRT and Theranostics. GenesisCare is about to commence the Telix TARGET trial, a phase 3 randomised trial of EBRT alone versus EBRT in combination with 177 Lu-PSMA in patients with biochemically recurrent prostate cancer.  This is the first trial using the combined approach of EBRT with Lu-177 PSMA molecular radiotherapy in metastatic prostate cancer. It is hoped this trial will help inform future protocols and guidelines in this area.

Some of the barriers to introducing a combined protocol include the fact that in most healthcare systems these treatments are currently delivered in different departments by different clinical teams and that combining MRT and ERBT increases the time it takes to plan and deliver treatment. There are also practical considerations, for example a patient who has received therapeutic amounts of radionuclides and who need to be treated immediately with radiation therapy may present radiation safety problems in a radiotherapy department.

Managing side effects and potential toxicities from a combination of EBRT and MRT is an also an area which will require further exploration as new protocols are developed.

Internationally, we are witnessing a growing recognition of the critical role of therapeutic radiopharmaceuticals in cancer medicine, which in turn will facilitate more complex combined treatments. While further prospective research and clinical trials are required, international combination protocols for MRT and EBRT should be prioritised to inform standard-of-care practices and enhance patient outcomes.


About the Authors

Professor Nat Lenzo

Professor Nat Lenzo is a Nuclear Medicine and Internal Medicine Physician and the Medical Director of Theranostics at GenesisCare. From 2001-2006, Nat was the inaugural head of the Western Australia PET/cyclotron service based at Sir Charles Gardiner Hospital.

In 2015, Nat founded Theranostics Australia which became part of GenesisCare in 2017 to complement GenesisCare’s radiation oncology services to cancer patients in Australia and internationally. The GenesisCare Theranostics team is committed to developing and using targeted molecular diagnostic imaging and therapeutic agents for the diagnosis and treatment of cancers, with a focus on cancers which are difficult to treat or are becoming resistant to conventional therapies.

With a strong track record in developing clinical and research services in the public and private sectors, Nat’s research interests are in new molecular imaging and targeted therapeutic agents in neurosciences and oncology. He is the co-investigator on a number of grants, a principal investigator in several multicentre clinical trials, and a co-author on over 80 peer reviewed publications, predominantly in the areas of molecular imaging and therapy in neuroscience and oncology.

Nadia Falzone

Nadia Falzone, PhD, is a Clinical Physicist at GenesisCare, and was previously a Nuffield Medical Fellow at the University of Oxford in the Department of Oncology. She recently joined GenesisCare as part of the Theranostics physics research team.

A highly regarded researcher and academic, Nadia’s research interests are in Medical Physics, Radiobiology and Targeted Radionuclide Therapy. Nadia trained as a Medical Physicist (HCPC, UK accredited) specializing in Nuclear Medicine and Radiation Oncology. She spent a decade working as a senior research fellow in the Department of Oncology, University of Oxford. Her research focussed on the dosimetric evaluation of novel targeted radiotherapeutics. Using a bottom-up approach (from single cell to organ level i.e. systems that span a wide range of spatial scales) and incorporating radiobiological modelling the aim is to better predict the clinical efficacy of targeted radiotherapeutics. She has co-authored on over 50 peer-reviewed publications, predominantly in the areas of radiobiology  and dosimetry of targeted radiotherapeutics.

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About Author

Professor Nat Lenzo is a Nuclear Medicine and Internal Medicine Physician and the Medical Director of Theranostics at GenesisCare. From 2001-2006, Nat was the inaugural head of the Western Australia PET/cyclotron service based at Sir Charles Gardiner Hospital. In 2015, Nat founded Theranostics Australia which became part of GenesisCare in 2017 to complement GenesisCare’s radiation oncology services to cancer patients in Australia and internationally. The GenesisCare Theranostics team is committed to developing and using targeted molecular diagnostic imaging and therapeutic agents for the diagnosis and treatment of cancers, with a focus on cancers which are difficult to treat or are becoming resistant to conventional therapies. With a strong track record in developing clinical and research services in the public and private sectors, Nat’s research interests are in new molecular imaging and targeted therapeutic agents in neurosciences and oncology. He is the co-investigator on a number of grants, a principal investigator in several multicentre clinical trials, and a co-author on over 80 peer reviewed publications, predominantly in the areas of molecular imaging and therapy in neuroscience and oncology.

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