Clinical characteristics of long-term survivors of pleural mesothelioma

doi:10.21203/rs.3.rs-4854892/v1

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Clinical characteristics of long-term survivors of pleural mesothelioma

https://doi.org/10.21203/rs.3.rs-4854892/v1

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Objective

To identify the clinical characteristics of long-term survivors (> 5 years) with pleural mesothelioma (PM) who had previously undergone curative-intent surgery.

Methods

A total of 121 patients with PM undergone curative-intent surgery following neoadjuvant chemotherapy between January 2006 and June 2016were enrolled in this study. Long-term survivors were defined as patients survived > 5 years from the date of diagnosis. We determined the incidence and clinical characteristics of long-term survivors.

Results

Of 121, 41 (33.9%) survived > 5 years from the date of diagnosis. The median age was 62 years. There were 35 males, 23 right-sided, the performance status (PS) was 0 in 40, and all were epithelioid subtype. Nine had partial responses to neoadjuvant chemotherapy, and 32 had stable disease. The median sum of pleural thickness at three levels was 8.2 mm, 25 patients underwent pleurectomy/decortication, 14 were pathological T1, 33 were pathological node-negative, and 2 had severe postoperative complications (Clavien–Dindo classification grade ≥ 3). Tumor relapse was observed in 31, and the relapse pattern was local only in 21, distant only in 2, and both in 8. Of 31 patients with tumor relapse, chemotherapy was performed in 30. Of the 41 long-term survivors, 24 died from PM, and 3 died from other causes. The median relapse-free survival was 51.4months, and the median post-relapse survival was 45.0 months.

Conclusion

In our cohort, 33.9% survived > 5 years after diagnosis. The clinical characteristics of long-term survivors were a good candidate (< 70-year-old, PS0), epithelioid subtype, tinner pleural thickness and an uneventful postoperative course.

pleural mesothelioma

long-term survival

curative-intent surgery

Pleural mesothelioma (PM) is a highly aggressive neoplasm arising from the parietal pleura. The treatment of PM is challenging, with a poor prognosis due to its remarkable invasiveness [1]. Although multimodal treatment (MMT), including surgery, is commonly performed in early-stage patients with PM with favorable cardiopulmonary function, therapeutic outcomes have not been satisfactory, with a median survival time of 7–33 months [2–4].

Various investigators have identified prognostic factors [5–6], such as histological subtype[2, 7–11], performance status (PS)[12], macroscopic complete resection (MCR) [2, 11], lymph-node metastasis, pleural thickness [2, 10], and tumor volume [8] in patients with PM who have undergone surgery. Since PM is a rare cancer with an extremely poor prognosis, only a few literature reports have focused on long-term survivors. This retrospective cohort study aimed to identify the characteristics of long-term survivors of PM who had been treated at our institution.

Study design

Between January 2006 and June 2021, 121 consecutive patients with PM who underwent curative-intent surgery after neoadjuvant chemotherapy (NAC) were enrolled in this study. Long-term survivors were defined as patients who lived > 5 years from the date of diagnosis. We gathered data on the incidence and clinical characteristics of long-term survivors of PM.

Ethics approval

The institutional review board at the Hyogo Medicine University (number 3921) approved this study on 25 November 2021. Due to the retrospective cohort design, the requirement for written informed consent for study participation was waived by the institutional ethics committee. Instead, the participants were given an opportunity to opt-out if they did not want their information to be used in this study. This study was conducted in accordance with the principles of the Declaration of Helsinki.

Therapeutic strategy

A MMT strategy was taken for all radiologically resectable patients with PM who could tolerate curative-intent surgery. NAC was performed prior to curative-intent surgery in patients who had undergone MMT. After completion of NAC, radiological examinations were performed to evaluate the response to NAC according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST)[13].

As previously reported [14], curative-intent surgery, including lymph-node dissection, was performed in patients without apparent tumor progression. Extrapleural pneumonectomy (EPP) was the only surgical procedure that we performed before September 2012. After September 2012, we attempted to perform pleurectomy/decortication (P/D) in all patients, and EPP was performed when it was the only procedure that could help us achieve MCR. After completion of curative-intent surgery, adjuvant radiation therapy was only delivered after EPP, and adjuvant chemotherapy also was only delivered after P/D. When the curative-intent surgery could not be performed due to the presence of T4 factor (e.g., mediastinal infiltration), curative resection was abandoned and then defined as an exploratory thoracotomy.

Clinical follow-up after MMT was performed every 3–6 months with radiological check-ups, including contrast-enhanced CT or PET/CT, for as long as possible. Recurrence was determined by a multidisciplinary team according to the radiological and pathological findings.

Data evaluation

Medical records, including operation notes and radiological findings in all long-term survivors, were collected. The c-stage, yield clinical (yc)-stage, and p-stage were assigned according to the Eighth Edition of the Tumor, Node, Metastases Classification proposed by the International Mesothelioma Interest Group and IASLC [15]. Pleural thickness measurements were performed according to previous reports, and the cutoff point (sum of the maximum of pleural thickness in each of three thoracic levels as < 13 mm or ≥ 13 mm) was determined as done in a previous report [15].

The recurrence pattern was defined as local recurrence, distant metastasis, or both. Local recurrence was defined as a recurrent lesion located in the ipsilateral thoracic cavity or chest wall or mediastinal lymph-node metastasis. Distant metastasis was defined as a recurrent lesion located only outside of the above-mentioned local recurrence.

The data cutoff date was December 31, 2022. Recurrence-free survival (RFS) was defined as the time from the day of surgery to the day of recurrence; patients without recurrence were censored at the time when they were confirmed to show no recurrence. Overall survival (OS) was defined as the time from the day of diagnosis to the day of death, and patients who were still alive were censored at the time when they were confirmed to be alive. The Kaplan–Meier method was used to assess OS and RFS.

GraphPad Prism ver.5 (GraphPad Software Inc., San Diego, CA, USA) was used to perform all statistical analyses.

Patient characteristics of long-term survivors

The median survival of all 121 patients for whom curative-intent surgery following NAC was performed during the study period was 39.8 months. Of all 121 patients, 41 (33.9%) survived > 5 years after diagnosis (Fig. 1: Kaplan–Meier curve). The clinical information on long-term survivors is shown in Table 1. The median age was 62 years (range: 37–71 years), and there were 35 (85.4%) males. The PS was 0 in 40 (97.6%) patients, and PM was right-sided in 23 (56.1%). Asbestos exposure had occurred or was possible in 32 (78.0%) patients. The therapeutic responses of NAC were partial response in 9 and stable disease in 32. Preoperatively, 22, 17, and 2 patients were yc-T1, 2, and 3, respectively, and all were yc-N0M0. The sum of preoperative pleural thickness was < 13 mm in 32 patients and ≥ 13 mm in 9.

The perioperative information about the long-term survivors is shown in Table 2. Of the 41 long-term survivors, EPP was performed in 16 and P/D was performed in 25. MCR was achieved in 40 patients. The median postoperative hospital stay was 27 days (range: 16–74 days). Postoperative complications were observed in 20 patients, of whom only two experienced postoperative complications worse than grade 3. All patients had the epithelial histological type. Postoperatively, 14, 7, and 20 patients were yp-T1, 2, and 3, and 33 and 8 patients were yp-N0 and 1, respectively. Of the patients who underwent EPP, 12 of 16 were able to complete postoperative adjuvant radiotherapy. Of the patients who underwent P/D, 23 of 25 patients were able to receive adjuvant chemotherapy.

Clinical course of long-term survivors

The postoperative courses of the long-term survivors are shown in Fig. 2. Among all 41 patients, tumor recurrence was observed in 31, of which 24 died of disease 1 died of other disease, and 6 survived with disease. Of the 10 patients without recurrence, 2 died of other diseases, and the remaining 8 are alive without recurrence. The median RFS in all 41 long-term survivors was 51.4 (range: 7.2–107.4) months, and the median OS was 87.4 (range: 60.21.5–149.1) months. Analysis of the relapse patterns showed that only local recurrence was observed in 21, only distant metastasis in 2, and both in 8 patients. Of 31 patients with recurrence, post-recurrence treatment was performed in all 31 patietns, and chemotherapy including immune checkpoint inhibitors (ICI) was administered in 30 patients. Of 30, 19 patients were administered ICI and all 6 alive patients with disease had good therapeutic response.

This study found that approximately 34% of patients who received multidisciplinary treatment, including surgery, were able to survive > 5 years after diagnosis. This finding may provide clues to improving the outcome of PM treatment, as no reports have analyzed the clinical information of a large number of long-term survivors. The individual postoperative clinical courses of the 41 long-term survivors in this study are presented in Fig. 2, which shows that the median RFS was very long as 43 months. This information indicates that both NAC and curative-intent surgery should have an important role in preventing tumor relapse. The data also suggests that MMT as NAC followed by curative-intent surgery is necessary to achieve long-term survival.

This study revealed that the long-term survivors had the following features in common: 1) epithelioid subtype, 2) younger age, and 3) good PS. These variables are well-known good prognostic factors in patients with PM who underwent curative-intent surgery [3–4]. Pastorino and his colleagues reported that age < 50 years predicted good prognosis and might be linked to the presence of germline mutations, such as BAP-1. In this cohort, 6 patients were < 50 years old and 17 were < 60 years old. Despite the lack of genetic information in this cohort, patients with less aggressive tumor behavior due to their genetic background might have been included in this cohort.

An unsolved issue of MMT treatment is declining PS after surgery due to its robust invasiveness. Consequently, the completion rate was not satisfactory in previous studies[17–18]. Conversely, the completion rate of MMT was 75% and 92% in the patients who underwent EPP and P/D, respectively, in this cohort. There are two possible reasons for this finding: either the patients had a good PS to achieve the completion of MMT, and the other is that the incidence of severe postoperative complications was much lower than that in the previous study[17–20]. The absence of serious complications may have contributed to the maintenance of PS and completion of MMT. In a prospective clinical trial of multidisciplinary treatment, including EPP in Japan, the mean survival time in patients who completed NAC, EPP, and RT was 39.4 months, which was significantly longer than that in the non-completed group (11.4 months) [17], supporting the idea that completion of MMT lengthens survival. Furthermore, it can be inferred that a good PS was maintained after surgery, as almost all patients were still treated after recurrence.

Recently, the IASLC staging committee mentioned that pleural thickness is much more correlated with survival than the c-T factor based on its database[15, 21]. Since the quantitative assessmentsr has been revealed more prognostic, T description was revised based on the pleural involvement and extent of invasion to the sum of pleural thickness at three levels [21]. We have also previously reported a postoperative RFS of 24 months and OS of 56 months in patients with a sum of pleural thickness at three levels of < 13 mm [10]. In our cohort, the median sum of pleural thickness at three lesions was 8.2 mm, indicating that these patients are predicted to have favorable survival.

In recent therapeutic advances in PM, the introduction of ICI should be noted. In 2018, nivolumab was approved as a second-line treatment for mesothelioma as it has a significant effect on treatment outcomes [22]. In this cohort, among 30 patients who received chemotherapy after tumor recurrence, ICI was delivered in 20 patients. Furthermore, nivolumab could achieve favorable disease control in most patients, suggesting that ICI may have contributed to a prolonged prognosis.

This study had several limitations that should be considered. First, this was a single-institution historical study. Second, patients with apparent tumor progression after NAC were excluded from the therapeutic stream of MMT in this cohort, which might have affected the clinical outcomes and be considered selection bias. However, our study goal was to describe the patient characteristics of long-term survivors on MMT, which we expected would help improve the therapeutic strategy for PM. In the future, we hope to identify the predictive factors of long-term survivors in patients with PM, regardless of therapeutic strategy.

From our cohort, approximately 34% of the patients survived > 5 years after diagnosis. We found that the clinical characteristics of long-term survivors were younger age, good PS, epithelioid subtype, thinner pleural thickness, achieving MCR, and an uneventful postoperative course.

PM: pleural mesothelioma

MMT: multimodal treatment

MCR: macroscopic complete resection

NAC: neoadjuvant chemotherapy

mRECIST: modified Response Evaluation Criteria in Solid Tumors

EPP: extrapleural pneumonectomy

P/D: pleurectomy/decortication

RFS: recurrence-free survival

OS: overall survival

Conflict of interest

All authors have declared no conflicts of interest.

Competing interests

There are no competing interests relating to this study.

Funding

None declared.

Author Contribution

MH and SH contributed to the design and conception of this study. MH, AN, TN, AK, KT, SM, and NK conducted the data collection and analyses. They also prepared the first draft of the manuscript. MF, KKitajima, KKuribayashi, KY, and TK supervised to prepare the manuscript. All authors commented on and critically revised previous drafts of the manuscript, and approved of the final manuscript.

Acknowledgement

The authors would like to thank Enago (www.enago.jp) for the English language review.

Data Availability

Data is provided within the manuscript or supplementary information files

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Tables 1 and 2 are available in the Supplementary Files section.

No competing interests reported.

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Version 1

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You are reading this latest preprint version

Clinical characteristics of long-term survivors of pleural mesothelioma

Status:

Version 1

Abstract

Figures

Introduction

Methods

Study design

Ethics approval

Therapeutic strategy

Data evaluation

Results

Patient characteristics of long-term survivors

Clinical course of long-term survivors

Discussion

Conclusion

Abbreviations

Declarations

Conflict of interest

Competing interests

Funding

Author Contribution

Acknowledgement

Data Availability

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1