(UroToday.com) The 2023 Society of Urologic Oncology (SUO) annual meeting held in Washington, D.C. between November 28th and December 1st, 2023, was host to the annual European Association of Urology (EAU) lecture presented by Dr. Christian Fankhauser, entitled: “From Incision to Intervals: Fine-Tuning Uro-oncological Follow-Up”.
Dr. Fankhauser eloquently thanked the SUO for the opportunity to deliver the annual EAU lecture and discuss the topic of evidence-based follow-up. He noted that during his presentation, he will be representing the EAU and, specifically, its urologic oncology branch, the ESOU, which organizes the annual EAU urologic oncology meeting, recently re-branded as uroONCO, as well as the EAU young academic urologists.
Born and trained in Switzerland, Dr. Fankhauser subsequently obtained his Master of Public degree from Boston, completed a fellowship in Manchester, UK, under the tutelage of Professor Noel Clarke, before returning to Lucerne, Switzerland.
Dr. Fankhauser noted that this past year has been challenging for Switzerland, a small, landlocked country. Recent years have been eventful, marked by the retirement of tennis legend Roger Federer and a critical bank merger between Credit Suisse and UBS, aimed at avoiding a financial crisis. These events have humorously led to suggestions of changing the Swiss national flag from a white ‘plus’ on a red background to a white ‘minus’.
On a more serious, solemn note, Dr. Fankhauser acknowledged and mourned the loss of a Swiss urologic oncology pioneer, Professor Urs Studer, who unfortunately passed away this past fall. As a surgeon-scientist, he was a role model in both Switzerland and internationally. Dr. Fankhauser noted that his legacy lives on through his students, who include Agostino Mattei, head at the Department of Urology in Luzern.
On a more positive note, despite these recent challenges, Switzerland has been named the most attractive country in the world by US News. However, Notably, Canada ranked second, Sweden third, and the United States came in fifth.
Dr. Fankhauser next delved into his main topic of discussion: urologic follow-up. While this is not a novel concept, nor does it necessarily need to be revamped, he emphasized that as our field evolves, it is a topic worth revisiting.
A framework to optimize oncological follow-up could be symbolized with rings: Strategic Thinking, Planning and Development, and Implementation and Execution. These rings may remind some of Simon Sinek's three circles, as detailed in his insightful book "Start with Why" – a book highly recommended by Dr. Fankhauser.
Firstly, the 'Why' of cancer follow-up is critical. We must ask ourselves, why do we monitor our patients? At certain stages of cancer, we have the potential for curative salvage treatments in the event of local or distant recurrences. Early detection and treatment can reduce the burden of therapy and, significantly, prevent or identify cancer-associated health issues early on.
Moving to the 'How,' our discussions often focus mainly on comparative effectiveness esearch, such as the most appropriate imaging or biomarkers to use. However, discussions on health services research or implementation research to discuss who best follows up our patients, be it doctors, nurses, and/or other professionals are less frequent.
In Dr. Fankhauser’s opinion, the impact of patient-reported outcome measures (PROMs) remains underappreciated. Consider a New York study that randomized chemotherapy patients to receive either standard care or additional monitoring via PROMs. The group monitored with PROMs demonstrated not only enhanced quality of life and fewer hospital readmissions but also an increase in survival rates. He proposed that these findings could extend to our follow-up procedures. By integrating standardized questionnaires into follow-up, we may achieve several results.
Lastly, the 'What' often leads us to debating subtle differences in follow-up schedules, such as whether to include the pelvis in a CT scan of the abdomen to catch recurrences at the earliest possible stage. But in addition to those debates, we should contemplate empowering patients to participate in their own care, directing them towards mental health or social support services, obtaining nutritional guidance, and managing any disabilities they may face.
Why is it essential to refine oncological follow-up? The urologic oncology world has transformed significantly in the past 50 years - this includes many WHYs, HOWs, and WHATs in urologic oncology follow-up. This is best exemplified by recent advances in the this and bladder cancer worlds.
In testis cancer, we've learned that metastatic germ cell tumors are curable with platinum-based chemotherapy. However, managing the associated short and long-term toxicities remains a challenge and a main goal of follow-up.
In metastatic cases, treatment currently follows the IGCCCG prognostication system. Dr. Fankhauser was involved in the most recent attempt at redefining these within the EORTC (Europe's equivalent of Alliance, SWOG, ECOG, or NRG), but led to minimal changes in classification. Treatment typically involves 3x BEP for 'good' prognosis and 4x BEP for 'intermediate/poor' groups. Therefore, it is of utmost importance to detect recurrence after stage 1 still in the IGCCCG good prognostic group, which requires only 3 cycles of chemotherapy.
Notably, stage 2 germ cell tumors can now often be cured solely through surgery. This has been known for non-seminomas but more recently the SEMS collaborators have showed excellent results in seminomas too.1
Focusing on the 'how' in testicular cancer, our understanding of recurrence detection is comprehensive. The TRISST trial suggests that a reduced schedule of MRIs, as opposed to CTs, is safe.2 Now with MRI, the frequency of imaging might be less critical, ensuring we don't lose patients during follow-up is vital. An interesting concept is similarly being explored in the Watchman trial at The University of Toronto, which investigates virtual follow-up clinics visits for these patients.
A particularly exciting development has been the evaluation of microRNA371 as a novel biomarker. In Switzerland, Dr. Fankhauser and colleagues are monitoring over 1,000 testicular cancer patients in a prospective cohort. By analyzing a subset of retrospectively collected serum samples, their team found that recurrences can be detected two months earlier than with standard methods. They are currently prospectively measuring microRNA371 in all patients with stage 1 patients undergoing surveillance. Setting a threshold for a positive result has been challenging. They used the miR-detect assay, which provides the so-called RQ value. Visually, they have chosen an RQ of 15 as their cut-off, a decision recently supported by a retrospective study from a German multicenter analysis.
Lastly, the 'what' in testicular cancer encompasses personalized follow-up protocols, considering various risk factors, recurrence sites, and timing and how to implement these in clinical practice. In Switzerland, nearly all patients in the previously mentioned prospective cohort study are now included, with over 1000 patients enrolled with the goal of specifically assessing toxicity. An unexpected benefit of such a cohort has been its role in community building among physicians, facilitating second opinions, and enhancing healthcare quality. To gather data for this cohort, Dr. Fankhauser employed a comprehensive PROMs approach on a tablet, involving over 100 questions per patient visit. While some might see this as excessive, he drew on the insights gained from the New York PROM study. In his opinion, this approach is invaluable for uncovering cancer-related health issues that might otherwise go unasked, prompting important discussions prompted by the PROMs. Addressing these toxicities and finding the right healthcare providers for our patients is a complex task, but it's a necessary starting point in our quest for solutions.
In bladder cancer, metastatic disease was traditionally seen as a ‘palliative’ condition, with no evidence to suggest that early detection and treatment improves survival. However, this perspective has recently shifted. The ABC meta-analysis revealed benefits not only for neoadjuvant but also adjuvant chemotherapy. Regarding adjuvant immunotherapy, there has emerging evidence that overall survival improves when adjuvant immunotherapy is administered to patients with microscopic metastatic disease, as identified using circulating tumor DNA (ctDNA).3 These findings support the notion that treating micrometastatic disease post-cystectomy can enhance overall survival, thereby justifying vigilant oncological follow-up in these cases.
The introduction of ctDNA has invigorated the 'how' in bladder cancer. Dr. Fankhauser highlighted a recent publication by Lindskrog et al in Clinical Cancer Research, with the following take home messages:
- ctDNA measured at diagnosis, following neoadjuvant chemotherapy or cystectomy is prognostic and outweighs many known prognostic factors
- Changes in ctDNA during neoadjuvant chemo can predict pathological downstaging
- ctDNA may detect recurrence up to four months prior to being visible on imaging
- It is possible but yet undefined how ctDNA derived information may help to select systemic and local treatment options
While this is fascinating, Dr. Fankhauser noted that should not always wait for future innovations like ctDNA, while we already have effective tools at our disposal such as radical cystectomy pathologic data. In an analysis of over 5,000 cystectomy patients, Dr. Fankhauser’s team was able to stratify the annualized hazard ratio of recurrence, based on the pathologic stage. This shows substantial differences between different cystectomy pathology outcomes and a rapidly declining risk of recurrence within the first two to three years following surgery.
This data and a further review of risk factors for recurrence, onset, site of recurrence, and guideline follow-up protocols revealed a surprising disconnect. Despite the varying recurrence risks, many guidelines recommend following ypT0 as intensively as T4N+ disease, inherently seems discordant. Unlike the risk-stratifying follow-up schedules in testicular cancer, bladder cancer guidelines don't typically personalize recurrence risk.
Moreover, while guidelines list several follow-up investigations, they lack specificity regarding MR versus CT, timing of evaluations, or the necessity of specific intravenous contrast phases. The recommendations on measuring vitamin B12 levels, bicarb levels, and other parameters are also poorly defined. Ideally, we should aim to provide more detailed and clear follow-up schedules. The plan is to start a similar prospective cohort study in Switzerland based on their experience in testis cancer as such a project may improve the overall quality of follow-up for current patients and provide valuable information on how to design improved follow-up protocols for future patients.
In summary, there is a pressing need to refine follow-up protocols across the board in urologic oncology. This is driven by significant changes in the WHYs, HOWs, and WHATs of virtually every urological cancer. It is crucial to evaluate these protocols within a structured framework, like the 3-cycle method proposed by Simon, rather than directly jumping to the WHAT cycle. This ‘leap’ is a common methodological error that can lead to oversimplification.
The integration of numerous emerging markers into clinical practice makes follow-up not only exciting but also increasingly complex and costly. Therefore, it is imperative to carefully weigh the risks and benefits of these new tools.
Presented by: Christian D. Fankhauser, MD, MPH, Professor, Consultant Urologist, Universität Luzern, Luzern, Switzerland
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 Society of Urologic Oncology (SUO) annual meeting held in Washington, D.C. between November 28th and December 1st, 2023
References:- Daneshmand S, Cary C, Masterson T, et al. Surgery in Early Metastatic Seminoma: A Phase II Trial of Retroperitoneal Lymph Node Dissection for Testicular Seminoma With Limited Retroperitoneal Lymphadenopathy. J Clin Oncol. 2023;41(16):3009-3018.
- Joffe JK, Cafferty FH, Murphy L, et al. Imaging Modality and Frequency in Surveillance of Stage I Seminoma Testicular Cancer: Results From a Randomized, Phase III, Noninferiority Trial (TRISST). J Clin Oncol. 2022;40(22):2468-2478.
- Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): A multicentre, open-label, randomized, phase 3 trial. Lancet Oncol. 2021;22(4):525-537.
- Lindskrog SV, Birkenkamp-Demtroder K, Nordentoft I, et al. Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up. Clin Cancer Res. 2023.