Upcoming: PhD defense Pascal Jonker

Thyroid cancer was newly diagnosed in approximately 900 patients in the Netherlands during 2023, across various histopathological subtypes. The spectrum ranges from indolent tumors to the most aggressive cancers known in humans. Each of these tumors has its own characteristics, clinical challenges, and requires different management strategies.

Strategies to reduce morbidity in papillary thyroid cancer management

The second section of this thesis focuses on strategies to de-escalate papillary thyroid cancer (PTC) management. PTC accounts for approximately 90% of new thyroid cancer diagnoses annually and has a 10-year survival that exceeds 90%. The incidence of PTC in the United States has nearly tripled over the last few decades without affecting mortality, suggesting overdiagnosis. The main challenge of overdiagnosis is preventing patients from undergoing unnecessary and potentially harmful treatments. Several strategies may be considered to de-escalate PTC management, aiming to reduce both morbidity, costs and carbon footprint, while improving the quality of life.

Observing instead of operating
Active surveillance is a concept known primarily from the management of low-risk prostate cancer. Pioneering studies initiated at the Japanese Kuma Hospital introduced this concept in 1993 as an alternative to early operative treatment for low-risk papillary microcarcinoma (PMC), defined as cT1aN0M0 without extrathyroidal extension. Approximately 90% of lowrisk PMC could be managed conservatively with active surveillance during a 10-year follow-up. However, the current experience with active surveillance outside Japan is limited. A better understanding of local factors such as patient characteristics, tumor biology, surgical complication rates, associated costs and cultural preferences is needed to evaluate the feasibility of implementing active surveillance in other regions across the world.

Targeted molecular fluorescence-guided imaging and spectroscopy to improve staging
Multiple clinical studies have demonstrated that molecular fluorescence-guided imaging (MFGI) and quantitative spectroscopy are safe tools for in vivo tumor detection. These techniques employ tumor specific near-infrared fluorescent (NIRF)-tracers to distinguish between tumor and normal tissue intra-operatively. MFGI and quantitative spectroscopy may improve the accuracy of central compartment staging over the gold standard of ultrasound (sensitivity 33%, specificity 93%), potentially reducing unnecessary prophylactic central compartment lymph node dissections (CLND) and associated morbidity in patients with PTC. In addition, MFGI and quantitative spectroscopy could enhance the detection of multifocal PTC. Aligning with de-escalation trends, American guidelines advocate hemithyroidectomy as definitive treatment for low-risk PTC patients.2 However, implementing American strategies may pose challenges in regions with higher incidences of aggressive tumor characteristics such as multifocal disease. While ultrasound remains the gold standard for pre-operative detection of multifocal PTC, its sensitivity (22%) and specificity (89%) are poor.10 Further research is needed to evaluate the feasibility of both techniques in detecting nodal metastases and multifocality, as no previous studies have investigated these aspects.

Predicting recurrence using a thyroglobulin blood test
Upfront identification of patients at risk of recurrent PTC is valuable for reducing the intensity of follow-up schemes and potentially minimizing overtreatment with adjuvant 131I. Early postoperative assessment in PTC management involves measuring serum thyroglobulin levels, which reflect residual thyroid tissue. Serial thyroglobulin measurements post-thyroidectomy is useful for detecting persistent or recurrent disease. However, thyroglobulin cut-off values for distinguishing between patients at high and low risk of disease recurrence remain uncertain. A better understanding of the optimal threshold for predicting the risk of postoperative recurrent PTC is therefore needed.

The unknown perioperative risks of patients with SARS-CoV-2 infections

The third section of this thesis was developed during the early days of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. At this time, university research facilities closed and most projects faced delays. We used the extra time created by these delays to address a critical issue surgeons faced: mitigating morbidity and mortality risks for patients undergoing surgeries, including thyroid cancer surgeries. A first study of patients with perioperative SARS-CoV-2 infections undergoing surgery in various health care systems worldwide reported an alarmingly high 30-day postoperative overall mortality rate of 24%.11 If correct, a perioperative SARS-CoV-2 infection would dramatically increase the mortality rate of patients undergoing any type of surgery, including thyroid cancer surgery. However, overestimating the impact of SARS-CoV-2 on morbidity and mortality would unjustly delay necessary surgeries, increasing the backlog of cancelled surgical procedures due to large numbers of SARS-CoV-2 positive patients requiring hospital admissions. Accurate estimation of mortality and morbidity associated with a SARS-CoV-2 positive status in surgical patients was therefore urgently needed. This could help inform perioperative decision-making, potentially reducing morbidity and mortality rates and preventing unnecessary pooling of cancelled elective surgeries, including thyroid cancer surgery.

Exploring current and new treatments for aggressive thyroid cancers

In the fourth section of this thesis, the focus changes to aggressive thyroid cancers. Poorly differentiated thyroid cancer (PDTC) accounts for approximately 5% of thyroid cancers. With a 5-year overall survival (OS) ranging from 62% to 85%, the survival rate of PDTC lies between that of differentiated (DTC) and anaplastic thyroid cancer (ATC). Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer and amongst deadliest solid cancer types in humans. The median survival is 6 months, with an 80% mortality rate within a year of diagnosis.

What is the added value of radiotherapy in PDTC management?
Local recurrence in the thyroid bed is responsible for 18% of PDTC associated deaths. Adjuvant radiotherapy might reduce local recurrence, especially in patients with micro- or macroscopic involved resection margins, but data supporting this hypothesis is lacking. Many patients are also treated with radioiodine ablation (131I), but true rates of 131I-resistance and their impact on survival are unclear. A better understanding of the benefits and associated morbidity of applied adjuvant treatment modalities in PDTC is needed.

Is aggressive treatment in ATC beneficial compared to palliative limited treatment?
Besides seeking new strategies to improve survival, the main challenge is adequate palliation and preventing suffocation due to locoregional tumor progression. Patients are treated by a multidisciplinary team with either supportive care, palliative limited treatment (LT) or an aggressive regime with multimodality treatment (MMT) consisting of combined surgery, radiotherapy, and systemic treatment (chemotherapy, targeted therapy or immunotherapy). A structured comparison of treatment benefits, surgical complications, systemic treatment toxicity, and radiotherapy morbidity between MMT and LT is unavailable. A better understanding of these factors will clarify whether the benefits of these treatment regimens outweigh their disadvantages.

The need for effective systemic treatment for patients with ATC
Although occasional individual successes have been reported following treatment with everolimus and vemurafenib, the effects of current treatment regimens on overall survival are poor. This underscores the high demand for therapeutic targets in ATC, ideally for clinical available targeted agents or immunotherapy.

Aims and outline of the thesis

The main aims of this thesis are:
1. To investigate strategies that may attribute to the de-escalation of PTC management.
2. To quantify the mortality and morbidity risks of SARS-CoV-2 positive patients undergoing surgical treatment, including thyroid cancer surgery.
3. To evaluate aggressive treatment regimens and explore novel therapeutic options in PDTC and ATC.