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Risk Stratification Is Helpful in Designing Follow-Up Strategy and Future Studies on Adjuvant Therapies: Response to the External Validation on the Chinese Alliance for Research in Thymomas Predictive Model of Recurrence

      To the Editor:
      Chiappetta et al.
      • Chiappetta M.
      • Sperduti I.
      • Lococo F.
      • et al.
      May follow up duration affect the effectiveness of a predictive nomogram model for thymic malignancies recurrences? Results from an external validation.
      provided a valuable validation of the predictive model for thymic malignancy recurrences after complete resection built from the Chinese Alliance for Research in Thymomas (ChART) database.
      • Liu H.
      • Gu Z.
      • Qiu B.
      • et al.
      A recurrence predictive model for thymic tumors and its implication for postoperative management: a Chinese Alliance for Research in Thymomas Database study.
      The validation set included 283 patients who underwent complete resection for stage I to IIIa thymoma/thymic carcinoma/neuroendocrine tumors. Of them, 85.2% patients (241/283) were categorized as being at low risk and 14.8% (42/283) as being at high risk of recurrence. This was similar to the ChART data set, which contained 80.9% and 19.1% patients in the low-risk and the high-risk groups, respectively. The results were also consistent with the ChART model, with a significant difference seen in disease-free survival (DFS) between the two groups (5- and 10-year DFS of 88.8% and 79.9% in the low-risk group compared with 77.3% and 47.7% in the high-risk group, p < 0.0001). Moreover, a significant difference in overall survival (OS) was also noticed between the two groups (5- and 10-year OS of 94.3% and 87.5% in the low-risk group versus 88% and 65% in the high-risk group, p = 0.001).
      • Chiappetta M.
      • Sperduti I.
      • Lococo F.
      • et al.
      May follow up duration affect the effectiveness of a predictive nomogram model for thymic malignancies recurrences? Results from an external validation.
      In the original study, median OS had not been reached at the time of the study in the low-risk group. Yet, there was a significant difference in 10-year OS between the low- and high-risk groups, being 91.6% versus 78.3% (p = 0.002) (Fig. 1). In addition, OS was not an end point in the predictive model, as patients who developed recurrence could still have prolonged survival owing to the relatively slow disease progression and potentially effective treatment. This could be seen in the marked differences between OS and DFS in the ChART data set and in the validation by our Italian colleagues. The 5- and 10-year OS after recurrence in patients treated with operation could reach 70.9% to 82.7% and 49.6% to 68.2%, respectively.
      • Hamaji M.
      • Ali S.O.
      • Burt B.M.
      A meta-analysis of surgical versus nonsurgical management of recurrent thymoma.
      And for nonresectable local recurrences, exclusive radiotherapy has been reported as an efficient treatment method with high response rates and 5-year survival rates as high as 80% reported in small retrospective series.
      • Urgesi A.
      • Monetti U.
      • Rossi G.
      • Ricardi U.
      • Maggi G.
      • Sannazzari G.L.
      Aggressive treatment of intrathoracic recurrences of thymoma.
      For such, relatively indolent, tumors disease recurrence would be a better index than OS for evaluation of management results in completely resected patients. The purpose of the ChART prediction model was to investigate a proper surveillance strategy for early detection of recurrent diseases and timely intervention in a small group of high-risk patients, thus, sparing most low-risk patients of unnecessary exposure.
      Figure thumbnail gr1
      Figure 1Overall survival in the low- and high-risk groups of patients with thymic tumors after complete surgical resection in the ChART database. ChART, Chinese Alliance for Research in Thymomas.
      We noticed that overall recurrence rates were merely 5.8% in the ChART series, in contrast to a much higher rate of 14.8% in the Italian series. In addition to the speculation that longer follow-up may be associated with higher recurrence encountered, other potential factors would include differences in geographic regions and also the constitution of tumor stage and histology classification among different data sets—both of which are key factors for predicting prognosis in the ChART study. Our result was similar to that of the study of the Japanese Association for Chest Surgery, in which, among 862 patients, only 67 (7.8%) developed recurrence.
      • Kondo K.
      • Monden Y.
      Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan.
      We also agree with Chiappetta et al.
      • Chiappetta M.
      • Sperduti I.
      • Lococo F.
      • et al.
      May follow up duration affect the effectiveness of a predictive nomogram model for thymic malignancies recurrences? Results from an external validation.
      that longer follow-up is necessary for patients with thymic tumors, especially for low-risk ones, as was suggested in the ChART model.
      In addition to proper surveillance, an equally important message from the ChART study is the stratification of high-risk patients for designing future studies on adjuvant therapies after surgery. Given the very limited number of events in low-risk patients, it seems both inefficient and unethical to consider adjuvant treatment in most patients with thymic tumors after complete tumor resection. And according to risk stratification by our predictive model, recurrence in the low-risk group was exclusively locoregional, and distant metastasis was mainly seen in high-risk patients. This would be helpful in searching for effective treatment modalities according to the failure patterns in different risk groups.
      For relatively rare and indolent tumors like thymic malignancies, joint efforts are needed for a better understanding of the disease and its management. The ChART predictive model is just one example of increasing global and regional collaborations seen in recent years. And the external validation by Chiappetta et al.
      • Chiappetta M.
      • Sperduti I.
      • Lococo F.
      • et al.
      May follow up duration affect the effectiveness of a predictive nomogram model for thymic malignancies recurrences? Results from an external validation.
      helps greatly by adding more evidence to our knowledge bank.

      References

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        • Sperduti I.
        • Lococo F.
        • et al.
        May follow up duration affect the effectiveness of a predictive nomogram model for thymic malignancies recurrences? Results from an external validation.
        J Thorac Oncol. 2020; 15 (e137-139)
        • Liu H.
        • Gu Z.
        • Qiu B.
        • et al.
        A recurrence predictive model for thymic tumors and its implication for postoperative management: a Chinese Alliance for Research in Thymomas Database study.
        J Thorac Oncol. 2020; 15: 448-456
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        • Ali S.O.
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        • Monetti U.
        • Rossi G.
        • Ricardi U.
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        • Sannazzari G.L.
        Aggressive treatment of intrathoracic recurrences of thymoma.
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        • Kondo K.
        • Monden Y.
        Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan.
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