08 November 2022

This final research blog will focus on two tests (liquid biopsies and patient-derived organoids) that are being trialled for the diagnosis and follow up of prostate cancer. There is also a spotlight on two novel therapeutic approaches (an immunotherapy agent and the MRNA vaccine) as well as two surgical techniques (the single port robot and image guided lymph node dissection).

Diagnostic tests

The term “liquid biopsy” refers to a non-invasive analysis of biomarkers in biological fluids (such as blood, plasma, urine and saliva) to allow for the detection and follow-up, of cancers, avoiding the limitations of invasive procedures and obtaining enough molecular information than those derived from tissue biopsies1. At this time it does not replace prostate biopsies used to make a diagnosis and stage prostate cancer. The liquid biopsy is able to give a snapshot of what’s known as the tumour microenvironment. Some of the biomarkers it analyses include circulating tumour cells, extracellular vesicles, circulating tumour DNA and RNA1.

Another diagnostic trend is known as patient-derived organoids. In this technique, tumour cells are taken from the patient and cultured or grown in the lab (in vitro) creating three-dimensional models that can inform clinicians about growth efficiency and morphological, histological, phenotypic, and genomic features of the cancer2.

Both techniques have diagnostic, prognostic, and predictive value which can help guide treatment strategies. Within the ever-expanding field of precision medicine these diagnostic techniques will be important to provide personalised molecular targeted therapies such as immunotherapy.

Therapeutic approaches

New classes of immunotherapy are emerging and being tested in clinical trials. A more recent immunotherapeutic treatment approach introduces bispecific T-cell engagers (BiTEs) used to treat metastatic castrate resistant prostate cancer. BiTE molecules are designed to activate the body's T-cells to target and eliminate cancer cells3. Currently Acapatamab is being trialled in conjunction with androgen receptor blockers or other immunotherapy drugs to target prostate-specific membrane antigen (PSMA)3.

Once the safety and efficacy of these new immunotherapy agents has been determined, a future treatment trend will see the initiation of these drugs prior to surgery (neoadjuvant therapy) in addition to after surgery (adjuvant therapy) as well as for advanced disease.

Another potential therapeutic option is the use of MRNA vaccines which has gained popularity due to COVID 19. Many resources and funding have been poured into researching this technology. This has led to optimisation of mRNA vaccine structure, stability, and delivery methods, and the associated advantage of personalised preparations, low manufacturing costs, and the fast and scalable production required for a patient group that often experiences rapid disease progression4. The mRNA-based vaccination has been shown to induce or boost an anti-tumour immune response. In the future these vaccines could be an effective treatment for patients diagnosed with early-stage cancer or in an adjuvant setting, but it appears unlikely that the vaccines will succeed as a standalone treatment for advanced cancers because of challenges regarding the highly immunosuppressive tumour microenvironment in this stage of cancer4.

Surgical techniques

Robotic surgery using the Da Vinci robot is one of the most commonly used operative approaches for radical prostatectomy across Australia. In this minimally invasive technique five small incisions are made on the abdominal wall, where ports are placed for the instrumentation to enter and allow for the surgeon to complete the operation. The next generation Da Vinci robot is the SP or single port which results in the patient only having a single surgical incision. This single robotic arm has several smaller arms that move out and travel in different directions guided by the urological surgeon. It is associated with a shorter hospital stay and catheterization time, and the need for postoperative pain medication is lower compared to the multiple port conventional approach and in early follow up trials has comparable perioperative, functional, and oncologic outcomes5. This technology has not arrived in Australia yet but will do in the near future. As with all new technology it is very expensive and has a steep learning curve.

A novel technique that has been described using the Da Vinci SP robot is the partial prostatectomy. It is considered as an alternative to focal therapy (with the same inclusion criteria) and the focal area of the prostate containing the cancer is removed through the bladder (transvesical approach). A single incision is made in the abdomen wall and a port is placed into the bladder. The small instruments are then able to enter the prostate through the base of the bladder. During surgery visualisation is aided by a specialised ultrasound probe which is able to locate the tumour based on pre-operative MRI scans. The technique caters for a very select group of patients who may benefit from more treatment than active surveillance and less treatment than a complete radical prostatectomy6. Benefits of this procedure include limited perioperative pain, a short recovery period with same-day discharge, and a similar catheter duration (3-7 days) to that of focal ablation6. Early results from this research have demonstrated low morbidity, and maintenance of functional outcomes such as return to continence and erectile function. Long-term follow-up is required to clarify the oncological control of this approach.

One of the reasons for recurrence of cancer after surgery (reflected by a rising PSA) is due to the spread of cancer to the lymph glands. Most surgeons will do a lymph node dissection routinely as part of the radical prostatectomy. Those with high-risk disease may have what’s known as an extended lymph node dissection, where a greater number of lymph nodes are removed, which is a therapeutic procedure but is also prognostic and can guide future treatments. When patients have return of disease after surgery the imaging study of choice is a PSMA Pet Scan which is able to light up the areas where prostate cancer cells may be hiding. Researchers have created a specialised probe that can be inserted into the abdomen at the time of robotic surgery7. 99mTc-PSMA-I&S is synthesised and administered intravenously the day before surgery. During surgery the drop-in gamma probe is able to visualise any lymph nodes which are harbouring prostate cancer cells real-time and guide the surgeon to their location for removal. This helps reduce recurrence of cancer after surgery. The limitation of this technique is that this image is not able to detect micro-metastatic disease (very small groups of cancer cells.)

Because prostate cancer is so common there is an abundance of funded research, which is encouraging, as diagnostic and therapeutic approaches are constantly evolving. It will be interesting to see whether immunotherapy will ultimately cure prostate cancer (regardless of stage) without the need for surgery. Will diagnostic tests be accurate enough to detect prostate cancer in younger men before cancer even has a chance to manifest and then prevented from forming with personalised targeted treatments? And if it was to form and caught early enough will focal minimally invasive surgical techniques be targeted enough to remove only the cancer cells with minimal damage to surrounding tissues. It has been a pleasure writing these research blogs about everything related to prostate cancer and I would like to thank all readers for your loyalty.

References

  1. Crocetto F, Russo G, Di Zazzo E, Pisapia P, Mirto BF, Palmieri A, Pepe F, Bellevicine C, Russo A, La Civita E, Terracciano D, Malapelle U, Troncone G, Barone B. Liquid Biopsy in prostate cancer management—Current challenges and future perspectives. Cancers. 2022; 14(13):3272.
  2. Servant R, Garioni M, Vlajnic T, Blind M, Pueschel H, Müller DC, Zellweger T, Templeton AJ, Garofoli A, Maletti S, Piscuoglio S, Rubin MA, Seifert H, Rentsch CA, Bubendorf L, Le Magnen C. Prostate cancer patient-derived organoids: detailed outcome from a prospective cohort of 81 clinical specimens. Journal of Pathology 2021; 254: 543-555.
  3. Marhold M, Kramer G, Krainer M, Le Magnen C. The prostate cancer landscape in Europe: Current challenges, future opportunities. Cancer Letters 2022; 526: 304-310.
  4. Lorentzen CL, Haanen JB, Met O, Svane IM, Clinical advances and ongoing trials of mRNA vaccines for cancer treatment. The Lancet Oncology 2022; 23(10): e450-e458.
  5. Li et al. Perioperative and oncologic outcomes of single-port vs multiport robot-assisted radical prostatectomy: A Meta-Analysis. Journal of Endourology. 2022. 36(1): 83-98.
  6. Kaouk JH et al. Single-port robotic transvesical partial prostatectomy for localized prostate cancer: Initial series and description of technique. European Urology 2022; 82(5): 551-558.
  7. Gandaglia G, Briganti A et al. Prostate-specific membrane antigen radioguided surgery to detect nodal metastases in primary prostate cancer patients undergoing robot-assisted radical prostatectomy and extended pelvic lymph node dissection. European Urology 2022; 82(4): 411-418.

About the Author

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Kalli Spencer

MBBCh, FC Urol (SA), MMed (Urol), Dip.Couns (AIPC)

Kalli is an internationally renowned Urological Surgeon, specialising in oncology and robotic surgery. He trained and worked in South Africa, before relocating to Australia where he has worked at Macquarie University Hospital and Westmead Hospital. His passion for what he does extends beyond the operating room, through public health advocacy, education and community awareness of men’s health, cancer and sexuality.

Kalli has been involved with the Prostate Cancer Foundation of Australia for many years, advocating for improved cancer care and facilitating community prostate cancer support groups.