Active surveillance: minimising treatment while maximising outcomes in testis cancer

As cure rates improve, the treatment paradigm in testicular cancer has shifted and research is now focused on allowing survivors to live longer and better, whilst minimising treatment and potential harm (1). These approaches rest on the repeated observations confirming the efficacy of treatment and importantly, preserved overall survival or ‘cure’, even if metastases develop (2-4).

First introduced in the 1980s, active surveillance for clinical stage 1 testicular cancer after orchidectomy has been embraced (5,6), and is now preferred to adjuvant therapy in most consensus guidelines (7-9). Whilst highly efficacious at preventing relapse (10-12), adjuvant treatment with chemotherapy or radiotherapy is associated with potential short- and long-term toxicities that may have persisting impacts on quality of life for long-term survivors and pertinently, is unnecessary for the majority (1). Attempts to stratify tumours using clinicopathologic features reduces the fraction exposed to unnecessary treatment (11), however based on contemporary data, even ‘high’ risk seminoma which has a relapse rate of 46% (13), will expose more than half the individuals to the perils of adjuvant treatment unnecessarily if uniformly applied.

Using an example of a young, otherwise well individual with a new diagnosis of T1b nonseminoma (i.e., no lymphovascular invasion), adjuvant treatment with a single cycle of bleomycin, etoposide and cisplatin (BEP) will improve the long-term relapse-free survival from 86.5% to 98.6% (11). However, the number needed to treat, to save one person from relapse approximates 8, and the cumulative number of chemotherapy cycles administered if an all-comer strategy is applied in the adjuvant setting, is greater than the number of definitive chemotherapy cycles recommended for those who ultimately relapse (assuming n=100, 100 × 1BEP + 1.4 × 3BEP =104.2 cycles vs. 0 × 1BEP + 13.5 × 3BEP =40.5 cycles). Whilst some may look favourably upon these numbers, the overall rate of cure remains unchanged, and the quality of survival of this often young population, should be forefront of our minds, with issues including cardiovascular morbidity, infertility, peripheral neuropathy, ototoxicity affecting survivors for decades after they are cured (1). While an informed discussion regarding the relative advantages and disadvantages of active surveillance and adjuvant therapy is encouraged (14), and selected clinical situations might move the pendulum towards adjuvant treatment (i.e., older age or other comorbidities that would make definitive chemotherapy challenging), limiting unnecessary chemotherapy (or radiotherapy) exposure is key to promoting long-term, quality survival of this population.

Active surveillance delicately navigates the risk of over-investigation and over-treatment, with the risks of recurrent testicular cancer, using a protocolised approach encompassing physical examination, regular imaging, and serum tumour biomarkers evaluation (6-9,15,16). These recommendations have been designed to proactively detect recurrences in the unlikely event they occur. However, there is room to improve surveillance protocols and Matulewicz et al. (17) prudently highlight three domains, which may herald forthcoming change.

Adherence to active surveillance recommendations is key to their success, however there is overwhelming evidence that adherence is sub-optimal (18). Strategies to optimise adherence, including shared care with primary health providers (which additionally offers enhanced preventative health care contact) (19), and use of Telehealth and/or health-based mobile applications offer opportunities to engage an often young and mobile population in their survivorship follow-up (20). Whilst Telehealth obviates an opportunity for physical examination of the contralateral testis, testicular self-examination can be encouraged as a surrogate between physical visits (21).

Due to the elevated risk of relapse in individuals not pursuing adjuvant treatment, an intensified imaging strategy is required, particularly during the first 24 months of follow-up. Whilst necessary to proactively detect relapse, this may reduce adherence due to impacts on time and/or finances in some jurisdictions, and exacerbate ‘scanxiety’ whereby fear of cancer recurrence is heightened in the lead-up to planned imaging (22). Additionally, concerns regarding radiation exposure have been raised. Strategies to de-intensify imaging in seminoma, including use of magnetic resonance imaging in preference to computerised tomography, reduction in scan frequency, and omission of pelvic imaging have been proposed and may address some of these challenges, and is reflected by some recommendations (6). Microribonucleic acids (miRNA), pertinently plasma miR-371, may obviate the need for frequent imaging in follow-up with a growing volume of evidence demonstrating superiority to existing clinical instruments and clinical utility in surveillance of both seminoma and nonseminoma with early detection of recurrence and high specificity and positive predictive value (23). Prospective studies are underway and are likely to cement this into active surveillance paradigms in the future (24-26). Unfortunately, miRNA have not yielded the same benefits in detecting teratoma (23), such that serial imaging cannot be replaced entirely, particularly in nonseminoma, which has an inherently higher risk of relapse compared with seminoma.

Despite these issues, active surveillance promotes an early return to ‘normal’ life, free from long-term toxicities and late effects, and balances the risks of recurrent malignancy in the setting of excellent salvage opportunities and most importantly, preserved survival (1).

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-364/coif). CC reports honoraria from Astra Zeneca. BT reports honoraria from Amgen, Astellas, Astra Zeneca, Bayer, BMS, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi and Tolmar, consulting fees from Amgen, Astellas, Astra Zeneca, Bayer, BMS, Ipsen, IQVIA, Janssen, Merck, MSD, Novartis, Pfizer, Roche, Sanofi and Tolmar, and grants from Amgen, Astellas, Astra Zeneca, Bayer, BMS, Genentech, Ipsen, Janssen, Pfizer, Movember and MSD. BT is the Chair of the ANZUP Germ Cell Tumour Subcommittee and this role is unpaid. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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