Management of patients with extensive locally advanced thyroid cancer: results of multimodal treatments

Thyroid cancer (TC) is the most frequent endocrine tumor, accounting for about 22 new cases per 100.000 people every year [1]. Malignant transformation can happen both in follicular and parafollicular thyroid cells. Differentiated thyroid cancer (DTC), that represents 90% of thyroid malignancies and includes papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC), originates from follicular cells, while medullary thyroid cancer (MTC) originates from parafollicular cells [2, 3].

Although an excellent prognosis has been widely recognized for thyroid malignancies [4], metastatic DTC, as well as specific hystotypes, namely, ATC, PDTC, or MTC, have worse prognosis [4, 5]. Durante et al. reported an overall survival of 42% at 10 years in patients with metastatic DTC at diagnosis, which dropped to 10% in radiorefractory cases [6]. In PDTC, the 5 year overall survival was recently reported to range from 63.6 to 72.8% [7, 8] and only one-third of patients reached clinical remission during their clinical course [8]. A slightly better clinical outcome was recently shown by Matrone et al. [9] in patients with MTC, although almost 50% of patients did not experience an excellent response during a median follow-up of 7 years.

Surgery plays a key role in the therapeutic management of patients with TC even in locally advanced or metastatic stage [4, 10]. In these latter cases, especially when the tumor is not confined to the neck, the role of surgical resection is still being discussed [11]. Moreover, the definition of locally advanced TC, albeit intuitive, is not standardized, as well as the definition of “unresectable” cases [11]. Finally, an extensive surgical treatment could be controversial both for technical issues and the risk of complications in patients who often present with multiple comorbidities [11, 12]. In these cases, systemic therapies could be considered and represent the standard of care [13].

The aim of this study was to share our experience, as a multidisciplinary team, in the management of patients with locally advanced TC with a particularly extensive local disease whose surgical treatment could be challenging and not resolving but at the same time necessary to make other medical treatments possible.

We retrospectively reviewed patients with locally advanced TC, in whom the surgical approach of the disease needed the presence of different type of surgeons (i.e. vascular, cardiovascular, endocrine, and thoracic surgeon) because of the local aggressiveness. All patients were preoperatively evaluated by a multidisciplinary team comprising of an endocrinologist, an anesthesiologist, and surgeons of these different specialties from January 2019 to June 2020. The cases included in the present study were only those in whom surgical treatment (although extensive) was considered feasible after multidisciplinary evaluation. Conversely, we excluded all the advanced cases in whom surgical treatment was not feasible according to the judgment of different surgeons.

We analyzed demographic, clinical, surgical, and pathological data of all patients using our medical records. All patients included in this study had a complete preoperative work-up. In this regard, they were evaluated with a total body CT-scan, neck ultrasound and, when necessary, gastroscopy, bronchoscopy, and cavography. As for policy of our hospital, all patients signed an informed consent for the use of their clinical and biochemical data for research purposes. They also signed an informed consent to proceed with the suggested interventional treatments. The present study has been approved by the local ethical committee.

Six patients with the above-described clinical features were identified. From a histological point of view, they were 2 PDTCs, 2 PTCs, and 2 MTCs. Four patients underwent major surgery, performed by a multidisciplinary team, including a thoracic and an endocrine surgeon (patients #3–6). In the other two cases (patients #1 and #2), vascular and cardiac surgery expertise was also necessary because of neoplastic vascular and cardiac involvement requiring the use of extracorporeal circulation (ECC), cardioplegia, and vascular graft placement.

In the last 20 years, the incidence of TC has progressively increased, especially since TCs with a diameter less than 1 cm are more frequently diagnosed [1]. However, many authors observed that diagnosis of TCs with a larger diameter (> 4 cm) presented a significant increase too, as well as cases with extrathyroidal extension and lymph-node metastases [15, 16]. If the challenge is to avoid overtreatment in very low aggressive cases [17], in patients suffering from advanced TC, the challenge is to be ideally radical, weighting a potential significant morbidity [11].

We reported our experience in advanced TC cases treated with a multimodal approach, including surgical, radiometabolic, and systemic therapies. We confirmed the crucial role of surgery in treating advanced TC, beyond its well-systemized role in cases confined to the neck region [18]. In our clinical series, surgery had a fundamental role in: (1) reaching a prompt symptoms resolution related to the metastatic disease, (2) allowing adjuvant therapies, not feasible or probably ineffective without a radical surgery, and (3) improving survival, as a component of a multimodal treatment regimen. On the other hand, in our series, both typical and atypical thyroid surgical complications occurred.

At admission, most of our patients presented symptoms related to the metastatic disease and, in particular, two of them mediastinal syndrome. As recently reviewed, mediastinal syndrome is very rare in TC, with a very poor prognosis [19]. Since 1879 onwards, about 60 cases of TCs with major vascular infiltration have been reported, and mediastinal vascular infiltration has been described in less than 30 cases [19‐21]. In our series, surgery allowed a prompt symptoms resolution related to vascular involvement and, during a median follow-up of 2.6 years, none of our patients developed symptom recurrence, confirming that surgery should always be evaluated in case of vascular infiltration or symptomatic patients [19]. Likewise, a massive tumor debulking should be taken into consideration in locally advanced MTC patients suffering from chronic diarrhea to reduce the complaints [22], albeit new target therapies have been demonstrated to be effective, too [23]. In our case, diarrhea disappeared immediately after surgery, without recurrence during a 3 year follow-up.

Beyond symptomatic relief, local disease control is one of the main oncologic targets of an enlarged surgery [11]. In a recent report of series including 153 DTCs with invasion of subcutaneous soft tissues, recurrent laryngeal nerve, larynx, trachea or esophagus, 5 year disease-specific survival, as well as locoregional recurrence did not differ between cases with complete resection (R0) and with positive margin of resection (R1) [24]. Furthermore, regional eradication or debulking of the tumor mass, resulting in macroscopically radical surgery or in minimal residual disease, can allow other therapeutic options. In particular, two of our patients after surgery could ultimately initiate treatments with MKIs that were not feasible before surgery because of the extensive venous thrombosis. Lenvatinib, cabozantinib, and other MKIs are strong inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) [25, 26]. Since VEGFR regulates endothelial function, it is not surprising that its inhibition predisposes to platelet activation and thrombosis [27, 28]. Bai et al. carried out an extensive meta-analysis about the risk of thromboembolic events during MKIs treatment in advanced TC, and observed an increased risk of arterial thromboembolic events [29]. In SELECT trial, a phase III trial evaluating progression-free survival (PFS), response rate, overall survival (OS), and toxicity of lenvatinib [30], venous thromboembolic events were observed in 5.4% of cases in the lenvatinib arm, and in 3.8% of cases in the placebo arm. Likewise, in EXAM trial, a phase III trial evaluating PFS, OS, objective response rate, and safety of cabozantinib, pulmonary embolism was observed in 2.3% of patients treated with cabozantinib, and in none of the patients in the placebo arm [31]. In line with this evidence, the multidisciplinary team decided not to start MKI in the case of such big thrombosis, while it was possible after its debulking.

Regional disease eradication or debulking could reinforce the effect of following systemic therapies, whose efficacy depends on tumor burden. An updated analysis of SELECT trial by Gianoukakis et al. showed different duration of response induced by lenvatinib according to the baseline diseases burden [32]. Radioiodine efficacy too has been related to tumor burden [33]. Song et al. showed that both biochemical and structural responses achieved after radioiodine treatment were poorer in patients with higher disease burden [34]. In our clinical series, some patients performed effective radioiodine treatments after surgery that was not decisive, but at least stabilized the disease that, in our opinion, is anyway a good clinical result in this type of patients.

In our series, despite their advanced stage and multiple comorbidities, we did not observe any perioperative deaths or any cancer-related deaths during a median follow-up of 2.6 years. Our results are in line with those of other reported series. Marcy et al. described 9 cases of TC characterized by neoplastic venous obstruction, drawn from a database of 1171 patients [35]. They argued that very invasive multimodal treatment including surgery should be performed to improve survival [35]. The same conclusion was reached by Hyer et al., who studied a series of 5 patients with venous obstruction [36]. However, this extensive surgery is not devoid of complications, both typical and atypical for endocrine surgery. About the former, 4 patients developed hypoparathyroidism and/or laryngeal nerve injury with vocal cord paralysis. However, it is well known that the risk of typical complications for endocrine surgery, such as hypoparathyroidism, is influenced by the extent of neck dissection [37, 38]. About the latter, 2 patients developed pulmonary embolism and 1 patient sternotomy dehiscence. Even though the incidence of deep venous thrombosis and pulmonary embolism is low after conventional thyroid surgery [39], in patients with diffuse neoplastic thrombosis or undergoing aggressive thoracic lymphoadenectomy the incidence is not negligible [12, 40]. All these information and evidences must be well known by the multidisciplinary team that, for these reasons, should include an expert endocrinologist in advanced TC, an endocrine surgeon with a great experience of TC and other highly experienced specialists, such as thoracic, vascular, and otolaryngologist surgeons, tracheobroncoscopist, anesthetists, and others specialists according to the extension of the disease and comorbidities of the patient.

Our experience in the treatment of very advanced TCs, particularly at local level, shows the effectiveness of an extensive surgery performed by a multidisciplinary team in controlling symptoms, allowing adjuvant therapies, and improving the survival of patients whose cases would otherwise be very difficult to manage. The planning of a well-defined therapeutic strategy by a multidisciplinary team and the simultaneous presence at the operating table of expert surgeons of different disciplines determined a favorable outcome. Still relatively young patients can gain significant benefits from this therapeutic approach, mainly a longer survival and a chronicity of the disease with whom they cohabit for a long time. However, this type of surgery is possible, and should be performed, only in expert tertiary referral centers for the management of TC.