Report from the European Society of Thoracic Surgeons prospective thymic database 2017: a powerful resource for a collaborative global effort to manage thymic tumours

Abstract

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OBJECTIVES

We queried the European Society of Thoracic Surgeons (ESTS) prospective thymic database for descriptive analysis and for comparison with the ESTS retrospective thymic database (1990–2010).

METHODS

Data were retrieved (January 2007–November 2017) for 1122 patients from 75 ESTS institutions.

RESULTS

There were 484 (65%) thymomas, 207 (28%) thymic carcinomas and 49 (7%) neuroendocrine thymic tumours. Staging (Masaoka) included 483 (67%) stage I and II, 100 (14%) stage III and 70 (10%) stage IV tumours. The new International Association for the Study of Lung Cancer/International Thymic Malignancies Interest Group tumour, node and metastasis (TNM) classification was available for 224 patients and including 177 (85%) stage I–II, 37 (16%) stage IIIA and 10 (4%) stage IIIB tumours. Chemotherapy as induction and adjuvant treatment was used in 14% and 15% of the patients. Radiotherapy was almost exclusively used postoperatively (24%). A minimally invasive surgical approach (video-assisted thoracic surgery/robotic-assisted thoracic surgery) was used in 276 (33%) patients. The overall recurrence rate was 10.8% (N = 38). Compared to the ESTS retrospective database, the increased prevalence of thymic carcinomas (from 9% to 28%) and neuroendocrine thymic tumours (from 2% to 7%), an increase in the use of minimally invasive techniques (from 6% to 34%) and a wider use of chemotherapy as induction (from 9% to 15%) and adjuvant (from 2% to 16%) treatment were observed in the prospective database. The introduction of a set of variables considered essential for the data use (‘minimum dataset’) resulted in an increased average completeness rate.

CONCLUSIONS

The reported data from the ESTS prospective thymic database confirm the recent trends in the management of thymic tumours. The ESTS prospective thymic database represents a powerful resource open to all ESTS members for the global effort to manage these rare tumours.

INTRODUCTION

The European Society of Thoracic Surgeons (ESTS) is the largest purely thoracic surgery society worldwide. Its aim is to gather the experience of thoracic surgeons from different continents in the different areas of thoracic surgery. One of the major initiatives of the society is the ESTS Registry, established in 2001 to collect the procedures the ESTS members use to treat lung cancer. After an initial limited number of procedures from only a few participating centres, the project has gained an increasing and steady push forwards, and the numbers of procedures and contributors have increased in recent years. The 2017 registry report included more than 110 000 patients with lung cancer from 240 participating units, and 145 contributing institutions reported using more than 100 procedures.

The ESTS registry was recently enhanced by adding some satellite databases to collate data of patients with other thoracic malignancies.

Among the ESTS satellite databases, the thymic registry was established in 2013 with the intent to collect the experiences of as many ESTS institutions as possible with an interest in thymic tumours. The thymic registry was the natural implementation of the initial ESTS retrospective thymic database, established in 2010, that was managed by the ESTS thymic working group and that collated data from 1990 to 2010. The unprecedented collection of data from the retrospective database represented a major contribution to the development of the eighth tumour, node and metastasis (TNM) staging system of thymic tumours [1], together with thymic databases from the International Thymic Malignancies Interest Group (ITMIG) and the Japanese Association for Research on the Thymus (JART), under the coordination of the International Association for the Study of Lung Cancer (IASLC). After the success of the retrospective database, the participants decided to launch the prospective thymic database project as a satellite database of the ESTS Registry platform with the intent to provide an up-to-date, online platform for collecting claims and electronic medical record data of patients with thymic malignancies from ESTS institutions. The prospective ESTS thymic registry is under the direct supervision of the ESTS Database Committee, and it is managed, audited and periodically maintained by KData Clinical (Rome, Italy) (formerly Dendrite), the official platform of the ESTS Registry.

Our goal was to present the results of the ESTS prospective thymic registry and to compare and discuss the currently available literature on thymic neoplasms and, with the ESTS thymic retrospective database, to highlight the trends in the presentation and management of thymic tumours in the ESTS community over the last several decades.

MATERIALS AND METHODS

We downloaded from the ESTS registry satellite thymic database all the cases from the prospective dataset. The collection of data started in 2010 and data from 2007 were retrieved through November 2017. The retrieved data (forming the ‘ESTS_Data Base_Thymus’ for the present study) were cleaned before the analysis. The rate of completeness and reliability rates of the core variables [2] were evaluated. The completeness and reliability measurements were obtained following a standardized method [3]. All the variables of interest were collected and analysed, and the completeness of the data for each variable for a preset number of variables considered ‘essential’ was recorded. These variables constituted the ‘minimum dataset’, which was defined as the minimum set of variables considered essential for the use of the patient record. The list of the variables of the minimum dataset is shown in Table 1.

The minimum dataset as well as information about the staging of clinical TNM (cTNM) and pathological TNM (pTNM) including the node (N) descriptor according to the ITMIG/IASLC nodal map was introduced and incorporated into the ESTS Thymic Registry in 2016.

RESULTS

From January 2007 to November 2017, a total of 1122 patients were registered in the ESTS thymic prospective database. The accrual rate increased steadily through the years, with an annual accrual of more than 160 cases in the last 3 years. A total of 75 institutions contributed to the database, including 62 from Europe, 5 from Asia (4 from Turkey and 1 from Thailand), 7 from South America (Brazil) and 1 from Africa (Morocco) (Supplementary Material, File S1). The distribution of the European centres by country is shown in Table 2. The mean number of patients/institutions was 15 (range 5–83). Table 3 summarizes the characteristics of the patient population.

Demographics and preoperative characteristics

The mean age at diagnosis was 54 years; 414 patients (37%) were older than 50 at diagnosis. There was an equal distribution between genders (50.2% men, 49.8% women). One-third of the patients (N = 216, 32%) had myasthenia gravis at diagnosis. A history of previous malignancy was recorded in 82 cases (15%), mostly breast (N = 13) and colon (N = 10) cancer. A preoperative cytological/histological diagnosis was performed in 21% of the cases (N = 115).

Histology and staging

The majority of patients had thymoma (N = 484, 65%); 207 (28%) had thymic carcinoma and 49 (7%) had neuroendocrine thymic tumours (NETT). In the thymoma group, 58% (N = 253) had low-risk tumours (A, AB and B1) whereas 183 (42%) had high-risk tumours (B2–B3). More than half of the patients (N = 399) presented with large tumours (> 5 cm). The most frequently involved structures at surgery were the perithymic fat/mediastinal pleura (N = 199, 30%), pericardium (N = 50, 8%), lung (N = 53, 8%) and brachiocephalic vessels/superior vena cava (N = 59, 9%). The clinical (pretreatment) and pathological (postsurgical) Masaoka stage was recorded. At surgery, 34% (N = 248) of the patients were at stage I, 33% (N = 235) at stage II, 14% (N = 100) at stage III and 10% (N = 70) at stage IV. In 24% of the cases, a clinical stage I was not confirmed pathologically. Clinical stage II was rarely recorded (N = 93, 17%), whereas pathological stage II (stage IIa/IIb) was reported much more frequently (N = 234, 33%). There was a good concordance between clinical and pathological stage III (N = 77–14, 1% vs N = 100–14.0%), stage IVA (N = 37–6.8% vs N = 45–6.3%) and stage IVB (N = 13–2.4% vs N = 25–3.5%).

Both clinical and pathological information about the IASLC/ITMIG TNM classification (8th edition) was available for 224 patients. More discordance was observed between cTNM and pTNM compared to cMasaoka and pMasaoka (Table 3). Percentages of cTNM and pTNM for the different T categories were as follows: T1: 70% and 56%; T2: 15% and 22%; T3: 10% and 16%; T4: 4% and 4.4%. A very low frequency of N+ disease was reported (3%, N = 7). The frequency of M disease was 7% (N = 17).

Surgical information

A complete resection was achieved in 89% of the cases (N = 710). The most frequent extent of resection included a complete thymectomy + thymomectomy (thymothymomectomy) in 90% of the cases (N = 682), whereas in 56 cases (7%) only thymomectomy was performed, leaving the thymus behind. Of these, 32 were patients with stage I–II tumours, which represents 6.6% of the entire stage I–II population (N = 483). The most frequently reported surgical approach was a full-length sternotomy (N = 389), which was performed in almost half of the patients (48%). Minimally invasive techniques were used in 33% (N = 276) of the patients, including video-assisted thoracic surgery (VATS) (N = 167, 20%) and robotic-assisted thoracic surgery (RATS) (N = 109, 13%). Extended approaches (sternothoracotomy, hemi- or clamshell) were reported in 5% of the patients (N = 41). The most frequently resected structures included the pericardium (N = 110, 18%), the mediastinal pleura (N = 93, 15%) and the phrenic nerve (N = 48, 8%). Resection of the great venous vessels was not infrequent (brachiocephalic veins: 24 cases; superior vena cava: 9 cases). As for the associated lung resection for pulmonary involvement (N = 112), the most frequent procedure was a wedge resection, which was performed in 98 cases. Anatomical resections were performed in 14 cases (segmentectomy, 1 case; lobectomy, 9 cases; and pneumonectomy, 4 cases). Very rarely were other mediastinal/thoracic structures resected. Pleural procedures for pleural involvement included resection of pleural implants (N = 14), diaphragm (N = 8) and extrapleural pneumonectomy (N = 3).

Perioperative treatments and outcome

Radiotherapy and chemotherapy were used perioperatively as an adjunct to surgery in different settings. Radiotherapy was used more often in an adjuvant (postoperative) setting in 164 patients (25%), whereas chemotherapy was evenly employed in the preoperative setting as an induction treatment (N = 69) and in the postoperative (adjuvant) setting (N = 71) in 15% and 16% of the patients, respectively.

The vast majority of patients were discharged alive from the hospital (N = 939, 99%). Five patients died in the hospital, and an additional 4 patients died at 30 days.

Overall, we had information about recurrence status in 451 patients. Of these, 49 patients experienced a recurrence (10.8% recurrence rate). Eleven patients presented more than 1 recurrence episode.

Data completeness

Figure 1 shows the completeness rate of the fields of the minimum dataset, which include the data fields that are considered essential for the use of the record for the analysis. The median completeness rate was 63.3%, ranging from 39.8% (chemotherapy) to 90% (World Health Organization histology).

DISCUSSION

The present manuscript presents the results of the ESTS prospective thymic database as of November 2017. It provides an overview of the clinical presentation, histology, staging and management of thymic tumours among 75 ESTS institutions.

Clinical presentation and preoperative assessment

In the present registry, thymic tumours occurred with almost equal frequency in men and women, and in one-third of the cases, they were associated with myasthenia gravis. These statistics are in line with those reported in the current literature [4–6].

An increased rate of extrathymic neoplasms in patients with thymic tumours was reported by Filosso et al. [7]. In our database, the overall rate of extrathymic tumours was 15%, of which breast and colon tumours were the most frequent primaries.

A preoperative cytohistological diagnosis has been required for many years. With the advancements in radiological imaging (last-generation computed tomography and magnetic resonance imaging), a preoperative cytohistological diagnosis of a suspected thymic tumour progressively lost its importance and is currently limited to the infrequent occurrence of an equivocal radiological image or the presence of a non-resectable tumour to begin induction treatment. This tendency had already been confirmed in a survey among the ESTS members and in the retrospective ESTS database [8], and it is further evident in the present report where 79% of the patients did not have a preoperative cyto/histological confirmation.

World Health Organization histology and staging

The prevalence of the 3 different types of thymic tumours (thymoma, thymic carcinoma and NETT) in the present database was 65%, 28% and 7%, respectively. The prevalences of thymic carcinoma and NETT were higher than the figures commonly reported in the literature. Most of the largest series in the literature reported a prevalence of thymic carcinoma of around 15–20% [9–11], with a far smaller prevalence for NETT (2–3%) [12, 13]. We have no clear explanation for this prevalence difference in our database. The difference might result from geographic distribution, dedicated referral or improved pathological expertise in differentiating B3 thymomas from a thymic carcinoma. The tumour distribution is also different from the one we observed in the ESTS retrospective database (1990–2010), where we reported a prevalence of 88% for thymoma, 9% for thymic carcinoma and 2% for the NETT [14, 15].

In this report, information about the new IASLC/ITMIG TNM classification was available for more than 200 patients. A good stage stratification was observed, although a wider discrepancy between cTNM and pTNM was observed (particularly for early stages) compared to the clinical versus the pathological Masaoka stage.

Surgical approach and management

A complete resection was performed in most of the patients (89%), which reflects the relatively high prevalence of stage I–II disease (67%). The extent of thymectomy consisted of resection of the thymic tumour only (thymomectomy) in 7.5% of the cases overall and in 6.6% of early stages (stage I–II).

Controversy still exists in the literature whether non-myasthenic patients with early stage (stage I–II) disease, thymomectomy alone (limited thymectomy) may be considered instead of the standard complete thymectomy + thymomectomy. A recent paper from the JART database [16] found that 22.5% (N = 289/1286) of patients with Masaoka stage I–II actually received thymomectomy only, leaving residual thymic tissue behind. A similar figure (24%, N = 251/1047) was reported by Gu et al. [17], who searched the Chinese Alliance on Research in Thymomas (ChaRT) database. An even higher rate of thymomectomies alone versus thymothymomectomy (39%, N = 295/762) was reported by Narm et al. [18], who explored the Korean Association for Research on the Thymus (KART) database. The JART and ChaRT studies found no recurrence rate differences between the 2 techniques. In the KART study, no recurrence rate difference was found in stage I, although a significantly higher recurrence rate was observed in patients with stage II undergoing limited thymectomy. The lower percentage of limited thymectomies (thymomectomy) in the ESTS thymic database may reflect the traditional standard approach, which has been used in Europe over the last decades, with a general perception that limited thymectomy may predispose one to postoperative myasthenia gravis or to a higher recurrence rate.

Comparison of clinicopathological characteristics between the European Society of Thoracic Surgeons retrospective and prospective databases

Table 4 shows the clinicopathological characteristics of the patient population in the ESTS retrospective and prospective thymic databases. The comparison may help clarify the trends over time in the ESTS community about presentation and management of thymic tumours spanning almost 30 years (1990–2017). Median age, gender distribution, association with myasthenia gravis, stage distribution (Masaoka stage), tumour size at resection and complete resection rate remained similar in the 2 databases. On the other hand, a significantly different distribution of the types of tumours (thymoma, thymic carcinoma, NETT) was reported in the prospective dataset, with an increased prevalence of thymic carcinomas and NETT. A significantly increased use of minimally invasive techniques (VATS and RATS) was reported (from 4% to 20% for VATS and from 2% to 13% for RATS) with a consequent decrease of the number of open access procedures. This finding is in line with that from the most recent series from the largest international databases [19], which demonstrated a steady increase in the use of minimally invasive techniques for thymic tumours in recent years. A recent paper investigating the JART database reported that 30% of thymectomies in Japan are currently performed using VATS [20]. A 20% prevalence of VATS was reported in a recent paper from the ChART database from 1994 to 2010, with an increase up to 40% in the last 3 years [21]. Finally, in the ITMIG database, of 2514 patients undergoing thymectomy for thymoma from 1997 to 2012, 461 (18%) were operated on using the minimally invasive approach (VATS or RATS), with more than 70% in the last 2 years [22]. We observed a wider use of perioperative chemotherapy treatments in the prospective database, both as induction and as adjuvant therapy (from 9% to 15% and from 2% to 16%, respectively). The progressive increase in the use of induction chemotherapy in recent years supports the conclusions of some recent large series [23] and meta-analyses [24] and reflects the wider compliance from the contributing institutions to the current guidelines [25]. Radiotherapy was similarly used in both databases, although with a slight reduction in the prospective data (25% vs 29% in the retrospective database). This finding indicates a general perception among the ESTS members of the positive effect of postoperative radiotherapy after resection of thymic tumours, which has not changed over the last decades and which seems to be confirmed by 2 recent meta-analyses [26, 27].

International involvement in the European Society of Thoracic Surgeons prospective thymic registry

The ESTS thymic working group and the ESTS Database Committee have been actively involved in the large international effort related to thymic tumours that took place in the first decade of this millennium. The leading thymic organization worldwide is the ITMIG, which was founded in 2010 with the aim to promote and facilitate cooperation among disciplines, societies and organizations with an interest in thymic tumours and to provide infrastructures and platforms to advance the clinical and basic research on these rare malignancies. A number of thymic organizations are also active worldwide working in collaboration with ITMIG: among these there are the JART, the ChART, the KART and the Réseau Tumeurs THYMiques et Cancer (RYTHMIC). The ESTS thymic working group was established in 2010 as a permanent working group of the ESTS. In the same year, the group launched the thymic retrospective database, calling for the participation of any interested ESTS institution. The structure of the retrospective database was designed in conjunction with ITMIG in order to have as many common data fields as possible to facilitate future common studies. The response to the retrospective thymic database was enthusiastic; 35 centres joined the project. Within a few months, the largest retrospective database of thymic tumours for that time was collected. At the same time, IASLC called for the participation of international thymic organizations for the second phase of the IASLC staging project for the 8th edition of the TNM classification of thymic tumours. As a consequence of the call, more than 10 000 cases were collected, including 1814 from ESTS. The ESTS contribution to the 8th edition of the TNM staging classification was recognized by IASLC. The ESTS thymic retrospective database provided material for several studies, both alone [14, 15] and in association with ITMIG [10, 11]. In 2013, the time was right for the creation of the prospective thymic database. The ESTS Council and the ESTS Database Committee approved and funded the prospective thymic database project as a satellite database of the ESTS Registry, using the official ESTS platform (Dendrite, later KData Clinical). The great advantage of the prospective database is the more complete collection of data and overall increased data quality. The ESTS prospective database is on line, user-friendly (see Supplementary Material, File S2 for instructions to access) and free to all ESTS members. It is maintained periodically; it uses standardized risk factors and outcomes; and it has the possibility to export data for internal use from individual institutions, acting as an institutional database. It also represents a benchmark of performance and data quality for the individual surgeon and for the institution. The ESTS prospective database also represents a unique opportunity for any ESTS contributor to propose studies using the data from the ESTS thymic registry. It provides ESTS members a great opportunity to contribute to thymic research using one of the largest thymic databases in the world. A study draft illustrating the scope of the project and the expected results should be sent to the ESTS Database Committee. The draft will be discussed by the committee members and, if accepted, the contributor will receive the data for the analysis. Our coauthorship policy is that 1 person from each centre that made a substantial contribution to the ESTS thymic registry will be included in any manuscript submitted using the ESTS thymic database under a list that allows each contributor to be linked to PubMed.

The structure of the ESTS thymic prospective database was designed from the retrospective database with the addition of new data fields about imaging, types of diseases and the new TNM staging system. Also, a big effort was undertaken in conjunction with ITMIG to harmonize the 2 databases, similarly to what was done for the retrospective database, for common projects. The result was the creation of a set of variables considered essential for the use of the record that are identical in format and wording between the 2 databases.

A major issue in all databases, and particularly in multi-institutional databases, is the rate of completeness of the data fields, which in most clinical databases ranges from 20% to 85%, depending on the variables. Inputting the data in the online prospective databases is often a stepwise process over different periods of time, usually done by trainees or junior doctors. This process results in the presence of many missing values, which decreases the quality of the database. The 2015 ESTS Database annual report of the thymic prospective registry indicated a mean completeness rate of 40% (range 29–90%), which was considered suboptimal. To address this issue, we introduced the concept of the ‘minimum dataset’, which includes a set of variables that are considered essential in order to use the record. The contributors are informed that their data cannot be used for studies in the case of incomplete information of the minimum dataset. Another tool to increase the completeness rate was the institution of the Clinical Care Analysis (CCA) dashboard, which gives the contributor a visual representation (in a dashboard) of his/her own data and their completeness. Finally, periodical timely reminders to the contributors (twice a year) were also considered of help to keep the momentum among the contributors. These implementations (the minimum dataset, the CCA dashboard and the biannual reminders) were proposed to the contributors and were introduced in 2016; consequently, the thymic report presented in the 2017 ESTS Database Annual Report resulted in a significant increase of the median completeness rate (65%, range 42–95%) compared to the previous year (median 51%, range 27–92%). This positive trend was also evident at the last evaluation for the present analysis as of November 2017 (Fig. 1).

The ESTS prospective thymic database is presently 1 of the 3 prospective thymic databases in the world, along with the ITMIG and the RYTHMIC.

IASLC has recently launched the third phase of the IASLC staging project for the 9th edition of the TNM classification of thoracic malignancies, including thymic tumours [28]. Once again, ESTS was asked to provide the data from the prospective thymic database to be analysed, along with those from the largest thymic organizations worldwide (ITMIG, JART, KART and RHYTMIC). The results of this big collaborative global effort will provide a solid background for the next revision of the TNM staging system of thymic tumours, expected in 2024.

Finally, it is worth mentioning that, similarly to what has been done for the Core ESTS Dataset for lung cancer, a possible further collaboration with Epithor (Register of Patients Operated on by a Thoracic Surgeon) is under discussion and it is likely to be finalized in the near future.

Strengths and limitations

Some limitations are associated with the present report. First, although prospective, the data collection remains heterogeneous and reflects different individual areas of expertise, including the lack of a centralized pathological review, and a non-uniform attitude towards perioperative treatments. Also, the relatively few cases with a detailed TNM classification make it difficult to provide sound evidence about the applicability and the effectiveness of the new staging classification. Finally, although a significant increase in the completeness rate was observed in recent years, some data fields still include a considerable amount of missing information, which may limit the use of these records for analysis.

On the other hand, this report presents the results of one of the largest prospective thymic databases in the world. The potential impact of the information and the continuous data upload provided by the use of the official ESTS platform guarantee good data reliability.

CONCLUSIONS

In conclusion, the results of the ESTS thymic prospective database confirm the general changes in presentation, diagnosis and management of thymic tumours that have been reported in the current literature, including a trend towards the widespread use of minimally invasive resection techniques and an increase in the use of chemotherapy, both in the induction and in the adjuvant settings. The present database may represent a valuable source of data that can be used for collaborative studies with other major thymic organizations and for the 9th revision of the TNM classification of thymic tumours.

Conflict of interest: none declared.

REFERENCES