Treatment optimization: Finding the best treatment option for patients
Sawyer Badiuk, MSc
Cancer is a highly complex disease and its treatments are no different. Neuroendocrine tumours (NETs) are a diverse group of abnormally dividing cells that originate from specialized neuroendocrine cells. These cells are found throughout the body and act similarly to nerve and endocrine cells; they receive signals from the nervous system and respond by secreting hormones through the endocrine system. For NETs, typical treatment options include surgery, chemotherapy, somatostatin analogs and targeted therapies. However, selecting the treatment type or combination of treatments is only the first step. To optimize treatment outcomes, careful consideration goes into selecting various aspects of treatment, such as the amount of treatment (prescription), delivery schedule, and length of treatment. These treatment aspects, not limited to those listed above, can be investigated and evaluated using clinical trials. Figure 1 shows the four main phases of clinical trials and the question they are trying to answer.
In recent years, a type of targeted therapy using a radionuclide labelled peptide (a group of amino acids) called peptide receptor radionuclide therapy (PRRT) with Lutecium-177 (177Lu) has shown superior efficacy in the treatment of NETs. NETs have an abundance of a specific receptor on the tumour’s surface that binds to the hormone somatostatin. These specific receptors can be targeted in PRRT by using a peptide similar to somatostatin. A phase 3 clinical trial that compared the safety and effectiveness of this new treatment (PRRT with Lu177) to the standard somatostatin analog that slows down hormone production . PRRT with 177Lu showed superior efficacy in midgut NETs that originate in the middle of the digestive tract and provided critical data for FDA approval. In this trial, each patient was given the same 4 cycles of PRRT therapy. These cycles refer to the delivery of a cancer drug followed by a short break to allow the body to respond and recover. This phase 3 trial proved that PRRT with 177Lu was a better treatment option than the standard, which led a research group in London, Ontario to investigate how it could be optimized.
Through the collaborative research efforts between Western University and the London Health Sciences Center (LHSC), a phase 2 clinical trial was performed investigating the optimization of PRRT treatment with 177Lu . Specifically, this research group sought to evaluate PRRT treatment for different types of NETs by applying both an adjustable prescription radiation dose and maintenance therapy. The radiation dose adjustment aimed to optimize the prescription dose for each patient and avoid under- and over-dosing, which can occur when a standard fixed dose is prescribed to all patients. Patients that responded to the initial dose-adjusted treatment then received maintenance therapy that aimed to continue to slow cancer growth and improve overall survival for advanced-stage cancer patients.
In the study, the administered 177Lu dose was adjusted depending on the patient’s kidney and liver function, the spread of disease to the liver and bones (metastasis), as well as, whether they have previously received chemotherapy or radioimmunotherapy. Previous treatment is an important consideration when selecting the prescription dose since they all contribute to the impact on the patient’s body. Forty-seven patients were included in the study and had a range of primary grade 1 and 2 NETs presenting in diverse anatomical sites, including midgut, pancreas, lung, rectum, and ovaries. The grade of the NET is determined by how fast the cells divide, and therefore, how quickly the cancer grows, as well as the portion of cancer cells that look like healthy cells. In clinical practice, there are three different grades of NETs, and the grade helps physicians predict how fast the cancer will grow and spread, which is used in the treatment decision.
Patients that responded to the initial treatment of PRRT with 177Lu qualified for maintenance therapy that included a low dose of 177Lu every 6 months for a total of 4 years, unless the disease started to progress. To evaluate how the cancer responded to treatment over time, computed tomography (CT) imaging was used to image the cancer 16 weeks before and after the initial PRRT and every 4 months after receiving the maintenance dose. Importantly, CT imaging allowed the research group to visualize the extent of the disease in the patient and evaluate its response to treatment.
Overall, this study was interested in the progression-free survival and the overall survival of the patients. Progression-free survival refers to the length of time that a patient lives with the disease, but it does not progress and worsen. After evaluating the treatment response for the 47 patients in the study, the research team found that the median progression-free survival was 47.7 months (approximately 4 years). The previous phase 3 trial mentioned above had reported a median of 28.4 months (approximately 2.4 years). Therefore, this study showed that the introduction of prescription dose adjustment and maintenance therapy proved to have increased effectiveness in cancer treatment.
Determining the best cancer treatment is a multi-step process. The two studies explored emphasize the importance of clinical trials. It is evident that the phases of clinical trials involved in cancer treatment are important and build off each other, as shown in Figure 1. The researchers at Western University and LHSC recognized the clinical potential of PRRT with 177Lu from the phase 3 study, then applied it in a phase 2 trial to investigate whether optimizing treatment for NETs using prescription dose adjustment and maintenance therapy was effective. Overall, the knowledge gained in this study has the potential to increase patient quality of life and survival, and furthermore, provides critical information that can be used to further develop improved NET treatments.
 Strosberg, J. et al. Phase 3 Trial of 177 Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 2017; 376 (2)
 Sistani, G. et al. Efficacy of 177Lu-dotatate induction and maintenance therapy of various types of neuroendocrine tumors: A phase II registry study. Curr Oncol 2021; 28 (1)