Introduction
It is important to note that cancer is among the most challenging issues in modern medicine and healthcare. Not all forms of cancer have the same degree of severity and mortality rate, but the most problematic ones require effective solutions. Metastatic castration-resistant prostate cancer is a type of prostate cancer that is resistant to castration and has no potent method of treatment. One of the highly promising and potentially effective treatment approaches is 177Lu-PSMA radioligand therapy or RLT. The aim and rationale of the given literature review are to improve understanding of the treatment modality, assess its effectiveness, analyze its underlying mechanisms of action, and highlight the recent developments. The research question for the given proposal is as follows: what are the important aspects of 177Lu-PSMA radioligand therapy (RLT), including patient stratification, the therapy protocol, concomitant medication, and follow-up of patients with metastatic castration-resistant prostate cancer? 177Lu-PSMA radioligand therapy is safe, effective, and compatible with other forms of treatment.
Literature Review
Although the 177Lu-PSMA radioligand therapy is not a thoroughly researched subject with minimal implementation in practice, the existing evidence is still substantial to make definitive conclusions on its efficacy. The recent evidence suggests that it is a promising method of treatment for the most problematic form of prostate cancer. It has an exceedingly high mortality rate across the globe (Sun et al., 2021). The prime target of the therapy is metastatic castration resistant prostate cancer or mCRPC, which is highly lethal with a survival period of fewer than 20 months (Fendler et al., 2017). The 177Lu-PSMA radioligand therapy utilizes prostate specific membrane antigen or PSMA or PSA ligands to target the cancerous cells (Fendler et al., 2017). The main reason is the fact that this type of metastatic cell expresses PSMA in a high abundance making them more targetable by RLT. A study suggests that “as for patients with mCRPC, treatment with 177Lu-PSMA-617 RTL and 177Lu-PSMA I&T gave better effects and caused fewer adverse effects than third-line treatment” (Von Eyben et al., 2017, p. 496). In other words, RLT results in fewer side effects and more improvements in patients’ well-being.
The general body of research done in recent years show a clear pattern in favour of 177Lu-PSMA radioligand therapy. Despite the lack of substantial understanding of the underlying mechanisms of action, the targeted specificity of the RLT makes it highly effective against castration resistant prostate cancer. It is well-known that PSMA plays a key role in making these cancerous cells uniquely distinctive from healthy cells, which is why ligand therapy is able to accurately recognize them. In addition, the metastatic nature of mCRPC makes it impossible to use conventional surgical methods of physical removal of tumours since the cells spread throughout the body. In other words, RLT’s domain of functionality across the body, coupled with its precise focus on the cancerous cells, is what makes 177Lu-PSMA radioligand therapy promising.
When it comes to evaluating the effectiveness of cancer treatment therapy, a wide range of factors need to be considered. These might include survival rate, tumour progression, metastatic spread rate, and adverse effects. 177Lu-PSMA radioligand therapy is proven to be “effective and safe,” but “the underlying mechanism of this phenomenon remains unclear” (Cao et al., 2021, p. 861). The research focused on evaluating RLT with positron emission tomography to observe PSMA showed improvements in tumour growth reduction and survival rate (Grubmüller et al., 2018). It states that the total tumour volume and overall survival rates among patients were highly correlated, and RLT led to major advancements in limiting and reversing the spread of mCRPC (Grubmüller et al., 2018). Therefore, it is evident that the therapy shows a great deal of promise when it comes to applying the underlying mechanisms in real practice.
It should be noted that the majority of studies in the existing literature mostly focus on the evaluation of 177Lu-PSMA radioligand therapy. Since it is a novel method of treatment of difficult forms of prostate cancer, the motivation behind such approaches is understandable. A wide range of studies uses different methods of evaluation ranging from overall survival rates to specific membrane receptors of the cells. Every form of evaluation reveals a strong potential of 177Lu-PSMA radioligand therapy in treating mCRPC.
However, mCRPC can take on many different forms, where a new metastatic spread can make the disease deadlier, such as bone or lymph node metastasis. A study conducted on the latter two forms shows that the “maximum percentage decline of PSA was median 92%.” (Von Eyben et al., 2019, p. 2451). In addition, “seventeen patients with relapse after LuPRLT who received rechallenge LuPRLT or ActPRLT had a better OS than five patients who received other forms for relapse treatment. LuPRLT gave mild and transitory adverse effects” (Von Eyben et al., 2019, p. 2451). In other words, even when cancer redevelops and survives the therapy, the subsequent treatment is better in terms of effectiveness and the lack of side effects. Thus, 177Lu-PSMA radioligand therapy can be reapplied in several instances, which is primarily due to its low toxicity. Treatments with high levels of adverse effects are less likely to be useful after the failure of the initial procedural attempt since the damage is already done. A subsequent treatment might have even greater risks associated with the therapeutic process, which is not the case with 177Lu-PSMA radioligand therapy.
Another possible question might arise in the case of the compatibility of RLT with other forms of treatment. The research evaluated the effectiveness of 177Lu-PSMA radioligand therapy among patients who received taxane chemotherapy previously with those who did not. Findings suggest that it “is a promising therapy in mCRPC, with encouraging outcomes and minimal associated toxicity seen in both our T-naïve and heavily pretreated patient cohorts” (Barber et al., 2019, p. 955). Thus, one can state that RLT is compatible with other forms of treatment, but using it directly after the diagnosis will still be better.
Moreover, the 177Lu-PSMA radioligand therapy is effective when assessed from a PSA-focused standpoint. It is reported that “46% of patients had greater than 50% PSA decline after 177Lu-PSMA RLT, and a higher proportion (75%) had any PSA decline after therapy” (Yadav et al., 2019, p. 281). Therefore, around half of the patients with mCRPC showed significant progress, whereas only a quarter of them had no benefit from RLT. Another study found that “a greater than or equal to 30% decline in PSA at 6 wk was associated with longer overall survival” (Gafita et al., 2020, p. 1476). In other words, PSA, which is a prostate-specific antigen used to monitor the treatment response, showed promising results for this type of cancer. The study was “retrospective and the single-centre experience” (Gafita et al., 2020, p. 1476). Thus, it is important to note that it could be even more or less effective.
Role in Australian Practice: Challenges
The prime area of interest in using 177Lu-PSMA radioligand therapy in Australian medical radiation science practice is prostate cancer. The disease is the most commonly diagnosed form of cancer among males, and it is the second most commonly diagnosed cancer among Australians (Cancer Australia, 2022). According to statistical data from 2021, 18110 men were diagnosed with prostate cancer, which comprises almost a quarter or 23% of forms of cancer among males (Cancer Australia, 2022). The lethality rate of prostate cancer for 2021 in 3323 men is 12% of all cancer-related deaths among the male population (Cancer Australia, 2022). Although 96% of men survive for five years after the diagnosis, it is important to note that the survival rate changes significantly if mCRPC is assessed separately (Cancer Australia, 2022). The main reason is that the average survival rate for mCRPC is 20 months (Fendler et al., 2017). Therefore, many people who die from prostate cancer are due to having mCRPC.
On the basis of the information provided above, 177Lu-PSMA radioligand therapy’s potential role in Australian MRS practice. It has the potential to save almost all 3000 men dying yearly from prostate cancer, with a realistic estimate being around 2250 due to 75% effectiveness (Yadav et al., 2019). Considering the fact that prostate cancer is one of the most common forms of cancer, the implication of the 177Lu-PSMA radioligand therapy is paramount. The therapy is proved to be safer and more effective than its alternatives, with a great deal of success in reducing PSMA (Cao et al., 2021). The current state of radiological practice in Australia is challenged by the fact there is a shortage of radiologists, which indicates that there are not enough professionals to do the imaging and radiotherapies (The Royal Australian and New Zealand College of Radiologists, 2018). Therefore, having highly effective and safe treatment measures is more critical than ever since prostate cancer is the most common type of disease with a growing trend.
Thus, prostate cancer occupies a leading place in the structure of oncological morbidity in Australian men. The frequency of its detection at various stages increases every year. Accordingly, the diagnosis of prostate cancer remains one of the most relevant areas of research in modern urology. Prostate cancer develops asymptomatically until reaching the advanced stage of the disease, which is a powerful incentive to search for informative diagnostic biomarkers. It is necessary to detect the disease at an early stage of development and assess the degree of tumour progression in order to timely prescribe therapy.
MRS Gaps: Prostate Cancer and PSA
In the context of the problem of early detection of prostate cancer in Australia, it is difficult to overestimate the importance of PSA, but its determination has limited possibilities as a diagnostic marker. In case of repeated increases in PSA levels, the patient will eventually undergo a biopsy, while high PSA values ​​​​sometimes do not correspond to the presence of prostate cancer (Yadav et al., 2019). The approach to treatment and management of patients with different forms of prostate cancer is different. In the case of non-aggressive prostate cancer, patients may be under active surveillance, and this form of cancer will not subsequently lead to death from this pathology. With the appointment for a patient with an aggressive form of prostate cancer, surgical treatment of the prostate gland becomes. The conclusion on the appointment of a patient for surgery is made on the basis of the data obtained from a biopsy of the prostate gland, indications for which is a PSA level above a certain level.
It should be noted that biopsy is an invasive procedure with a number of complications. As a result, the differential diagnosis of prostate cancer forms is considered a necessary and promising area of ​​science. 177Lu-PSMA radioligand therapy is moving every day towards new, more specific markers or a complex consisting of several markers of prostate cancer in the diagnosis of aggressive forms of prostate cancer (Grubmüller et al., 2018). It is this approach that will help improve the accuracy of diagnosis in the early stages of the development of a malignant process. This will thus improve the selection of patients for primary or repeat biopsy, as well as identifying clinically significant prostate cancer requiring immediate treatment.
To assess the objective effect of the treatment of prostate cancer with bone metastases, X-ray data, computed or magnetic resonance imaging, and radioisotope bone scanning (Barber et al., 2019) are used. Assessment of the subjective effect of treatment is carried out according to the characteristics of the patient’s condition before the start of treatment, during treatment, and after its completion. The latter includes the reduction or disappearance of pain and an increase in body weight. Reliable determination of the stage of prostate cancer is important for the choice of treatment tactics. Radical prostatectomy and interstitial radiotherapy (brachytherapy) are only possible with localized primary cancer. Remote gamma therapy is indicated for patients with locally advanced tumours. The combination of radiation treatment with hormone therapy increases the survival rate of patients. With generalized prostate cancer, various options for androgen blockade are used.
Despite the high efficiency, the use of estrogens is limited due to severe side effects. Surgical castration as an independent type of treatment is rarely used when other methods of hormone therapy are not available. LH releasing factor agonists have replaced orchiectomy. The most common is maximal androgen blockade, such as the combination of agonists and antiandrogens (Yadav et al., 2019). It has shown high efficacy in patients with generalized PCa and is recommended as first-line therapy for the treatment of this category of patients (Fendler et al., 2017). Despite the rather high efficiency of the maximum androgen blockade, its side effects are significant. Monotherapy with antiandrogens is less toxic and has an advantage when it comes to maintaining sexual activity or reducing treatment toxicity.
In the prostate gland of one patient, areas of tumour tissue with different degrees of differentiation can be found. The degree of malignancy of prostate cancer, according to Gleason, is determined by adding the two areas of the tumour that are the predominant area. The higher the grade, the greater the risk of local spread (Von Eyben et al., 2017). There are no symptoms in the early stages of the disease. In the later stages, symptoms of lower urinary tract obstruction, dysuria, bone pain, and sexual dysfunction are the reason for seeking medical attention. The disease is detected by digital rectal examination, determination of the level of prostate-specific antigen in the blood, and transrectal ultrasound (Von Eyben et al., 2017). The method of clarifying diagnosis is a targeted multifocal prostate biopsy followed by a morphological study. In order to determine the stage of cancer, a radioisotope scan of the skeleton, X-ray of the chest and pelvic bones, abdominal ultrasound, and computed tomography of organs suspected of being affected by metastases are performed (Fendler et al., 2017). The result of the diagnosis is the establishment of the stage of the disease according to the standardized system.
Discussion
Prostate cancer (PC) occupies a leading position in the structure of malignant neoplasms (MN) in middle-aged and elderly men. The main marker of biochemical relapse after specialized treatment is an increase in the level of prostate-specific antigen or PSA. Diagnosis of recurrent prostate cancer is currently a challenge for instrumental imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) due to the lack of sensitivity and specificity of these methods. A modern alternative to detecting recurrent prostate cancer is positron emission computed tomography (PET/CT) with choline derivatives. The results of a number of recent studies indicate some decrease in the sensitivity and specificity of PET/CT, especially with a low PSA level and a large standard scale.
In this regard, the development of alternative methods for the early diagnosis of prostate cancer recurrence at the preclinical stage is a modern priority. Recent studies have shown that prostate-specific membrane antigen can become a marker for the diagnosis of prostate cancer recurrence (Fendler et al., 2017). Prostate-specific membrane antigen, or glutamate carboxypeptidase II, N-acetyl-a-linked acid dipeptidase I, or folate hydrolase, is a type II transmembrane glycoprotein belonging to the M28 peptidase family. This protein acts as a glutamate carboxypeptidase on a variety of substrates, including nutritional folate and the neuropeptide N-acetyl-L-aspartyl-L-glutamate (Fendler et al., 2017). The PSMA protein has a unique structure consisting of 3 parts such as an internal part (19 amino acids), a transmembrane part (24 amino acids) and an external part, including 707 amino acids (GrubmĂĽller et al., 2018). PSMA is one of the most representative markers of prostate cancer since this antigen is highly expressed and highly specific on the surface of tumour cells that develop from the prostate gland at all stages of the disease.
PSMA is located in the cytosol of pancreatic cells, and in a malignant process, it is associated with a membrane protein. The level of PSMA expression correlates with a decrease in the degree of tumour differentiation and is more often elevated in metastatic and hormone-refractory tumours of the pancreas (Yadav et al., 2019). Thus, PSMA is a well representative target for prostate cancer imaging. It is possible to use PSMA ligands to diagnose prostate cancer using single-photon emission computed tomography.
Conclusion
In conclusion, 177Lu-PSMA radioligand therapy can be considered highly safe, outstandingly effective, as well as compatible with other forms of therapies. Firstly, RLT shows mCRPC specificity due to the PSMA targeting approach. Secondly, RLT has fewer adverse effects and toxicity compared to the typical cancer treatment measures. Thirdly, 177Lu-PSMA radioligand therapy is highly effective against mCRPC, where almost half of the patients experience significant improvements and 75% benefit from it in general. Fourthly, the current Australian MRS practice is faced with a growing trend of prostate cancer cases and a shortage of workers, which is the novel methods, such as RLT, are even more needed.
Thus, a review of existing literature shows that, despite advances in the surgical treatment of prostate diseases, the anatomical rationale for sparing surgical interventions remains an important problem today. The role of age-related differences in the surgical anatomy of the prostate and topographic and anatomical relationships of its diverse structures with the bloodstream remains unresolved. The three-dimensional spatial organization of the aggregates of the human prostate in its various zones and the architectonics of the excretory ducts have not been studied.
The development of programs for early diagnosis and screening of prostate cancer is one of the priority areas for the development of oncology and can significantly improve the results of treatment of this disease. Australia now has a centralized screening system for the male population for prostate cancer screening. In order to develop national guidelines, multicentre studies involving large Australian populations should be conducted. The high coverage of the male population by the screening program is explained by the attraction of financing from the local budget when the program in the country is based on the functional basis of the existing bases.
Serum PSA measurement is important and is a highly sensitive and effective method for detecting prostate cancer. It is necessary to carry out screening for prostate cancer allows increasing the percentage of detection of early stages of prostate cancer and radical surgical interventions. Subject to this trend, a decrease in cancer mortality in patients with prostate cancer is expected in the future. Continued screening programs are needed to evaluate mortality, economic costs, the effectiveness of prostate cancer screening in Australia, and to develop national guidelines. State financing of screening programs at all levels is essential.
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