Impact of Salvage Surgery and Re-irradiation for Radiation …

Title of the Poster Presentation Goes Here Authors of the Poster Presentation Goes Here Institutional and/or Graduate School of Biomedical Sciences Affiliation Goes Here Impact of Salvage Surgery and Re-irradiation for Radiation Failed Recurrent Skull Base Meningiomas Franco Rubino MD 1 ; Solon Schur MD 1 ; Susan L. McGovern MD 2 ; Carlos Kamiya-Matsuoka MD 3 ; Franco DeMonte MD 1 ; Shaan M. Raza MD 1 1 Department of Neurosurgery, Division of Surgery, MD Anderson Cancer Center; 2 Department of Radiation Oncology, Division of Radiation Oncology, MD Anderson Cancer Center; 3 Department of Neuro-oncology, Division of Cancer Medicine, MD Anderson Cancer Center

Introduction and objective: Long-term follow up of meningiomas has demonstrated recurrence rates of up to 60% after 15 years. There is limited data available to guide the management of recurrent and previously radiated skull base meningiomas and challenges related to salvage surgery, re-irradiation and lack of clear systemic therapy strategies remain. In this study, we analyzed data from our experience with recurrent and previously radiated meningiomas to assess the impact of salvage surgery and re-irradiation on PFS. Methods: A retrospective cohort study of 48 patients with recurrent and previously radiated meningiomas who were treated between 1995 and 2021 was conducted. Data were extracted from medical records and include clinical, radiologic, and pathologic reports. Patients were clustered according to WHO grades. We analyzed the complications related to re-irradiation and salvage surgery and the impact of different treatment modalities on PFS using Cox proportional hazard ratios .

As seen in Table 2, patients with WHO grade 1 meningiomas who underwent a STR had a 3.4-fold increase of disease progression compared to patients where GTR was achieved (HR 3.38; 95% CI, 1.268-9.03; p=.0189) (Figure 2, D). For WHO grade 2 and 3 patients however, EOR was not associated with differences in PFS (Figure 3, B andD).

Table 2 . Univariate Analysis of prognostic factors affecting PFS

Median PFS (months)

UNIVARIATE ANALYSIS

HR CI (95%)

P-Value

Patient demographics Age

<60 years-old ≥60 years -old KPS 90-100 KPS 60 - 80

Ref 1.68 Ref 2.61 Ref

Ref

30 11 26 15 20 7

1.156 -2.443

0.0025

KPS

Ref

1.510 - 4.50

˂0.0001

Gender

Female

Ref

Male

1.288

0.8564-1.938

0.971

Tumor features Location

AF/MF/PF/Combined

0.2535

Form

Globoid

Ref

12 20 30 12

En-Plaque

1.001

0.7012-1.429

0.1968

WHO grade

WHO 1 WHO 2 WHO 3

Ref

1.972 3.563

1.269 - 3.067 1.628 - 7.798

0.0002 ˂0.0001

KI- 67

KI-67 0-9% KI- 67 10 -19% KI- 67 ≥20%

Ref

51 12

2.285 3.426

1.249- 4.178 1.771- 6.628

0.003

˂0.0001

Treatment Related Variables Type of reRT SRS

Ref

28 36

EBRT

0.8507

0.5280-1.371

0.483

Treatment Modality WHO I

Ref

23 28 32

0.162

SX + reRT

- - -

reRT

Systemic Therapy

14.5

Treatment Modality WHO II

Ref

Figure 2. A: Progression-free survival (PFS) according to WHO grades, asterisk indicates a statistically significant difference (p=<.0001). B: PFS according to age, asterisk indicates a statistically significant difference (p=.0025). C: PFS of WHO grade 1 radiated meningiomas by different treatment modalities (p=.162), SX (surgery), reRT (re-irradiation). D: PFS of WHO grade 1 radiated meningiomas by extent of resection (EOR) (p=.0087). When looking at the impact of re-irradiation, WHO grade 3 patients who were re-irradiated were significantly less likely to progress over the course of the study (HR 0.27; 95% CI, 0.078-0.975; p=.0028 ) (Figure 3, C). Furthermore, adjuvant re-irradiation of subtotally or totally resected WHO grade 2 meningioma patients decreased the likelihood of disease progression over the course of the study (HR 0.316; 95% CI, 0.1304- 0.7682; p=.0029 for STR+RT and HR 0.259; 95% CI, 0.099-0.6747; p=.0048 for GTR+RT). (Figure 3, A). Repeat radiation was not found to be associated with improved PFS in WHO grade 1 meningioma patients (Table 2).

SX + reRT

0.365 0.457

0.175 - 0.757 0.218 - 0.959

41 22 18

0.0008 0.0238

reRT

Systemic Therapy 1

Treatment Modality WHO III

Ref

5.5

SX + reRT

0.653 0.276

0.184-2.32 0.078 - 0.975

0.468 0.0028

reRT

EOR in WHO I

GTR

Ref

123

STR +/- reRT

0.2760 0.1272 - 0.5987

0.0087

EOR in WHO II

GTR +/- reRT 2 STR +/- reRT 3 GTR +/- reRT STR +/- reRT

Ref

0.8919

0.4321-1.841

0.139

EOR in WHO III

Ref

5.5

1.649

0.5297-5.132

0.299

1 Only 3 patients, unpowered for statistical purposes 2 GTR + reRT = RR 0.259, 95% CI 0.099-0.6747, p=.0048, Median PFS=27 months 3 STR + reRT= RR 0.316, 95% CI 0.1304-0.7682, p= .0029, Median PFS=52 months Bold letters indicate statistical significance

Conclusion: We presented a retrospective analysis with the largest cohort of radiated and recurrent skull base meningiomas. According to our results, achieving GTR is the best option for recurrent WHO grade 1 meningiomas, radiation is the best option for WHO grade 3 meningiomas, and radiation appears to provide a benefit in subtotally resected WHO grade 2 meningiomas. Reoperation for recurrent skull base meningiomas is associated with a higher complication rate. Further prospective studies are needed to validate our results.

Figure 1. Diagram outlining patient selection

Results: • Patient Demographics and number of recurrences Forty-eight patients (33 WHO grade 1; 11 WHO grade 2; and 4 WHO grade 3) were treated for 143 recurrences after their first radiation treatment. Although patients with higher grade meningiomas seem to have lower KPS at recurrence, there was no significant association between KPS and recurrence rate ( X 2 [1, N = 143] =3.52, p=.06 ). The overall survival rate was 56.2% after a mean follow-up period of 12.4 ± 7.6 years, with 21 patients with stable disease and 6 patients in hospice. Twenty patients from our cohort (41.6%) had histologic progression (Figure 1 and Table 1).

Table 1 . Treatment Outcomes

Figure 3. A: Progression-free survival (PFS) of WHO grade 2 radiated meningiomas by different treatment modalities, asterisk indicates a statistically significant difference (reRT alone vs SX alone; p=.0238 and reRT+SX vs SX alone; p=.0008 ). B: PFS of WHO grade 2 radiated meningiomas by extent of resection (EOR) ( p=.139 ). C: PFS of WHO grade 3 radiated meningiomas by different treatment modalities, asterisk indicates a statistically significant difference ( p=.0028 ). D: PFS of WHO grade 3 radiated meningiomas by EOR (p=.299 ). Discussion: To our knowledge, this is the largest reported cohort of post-radiation recurrent skull base meningiomas summarizing the impact of salvage surgery and repeat radiation on tumor control rates. The management of post-radiation recurrence is not clear, but the decision should consider the WHO grading, along with the multidisciplinary treatments available. For WHO 1 meningiomas, despite the challenges associated with previous radiation, we found a clear benefit of GTR over STR alone or combined with RT. The impact of EOR on outcomes for WHO grade 2 meningiomas remains unclear and is even less effective in malignant meningiomas. One hypothesis to explain the lack of correlation between EOR and PFS could be the more aggressive behavior and a higher proliferative index labeling in tumors that recur versus tumors that don’t recur 1 . Furthermore, previous radiation might be a risk factor to increase the aggressiveness of the tumor 2 . This study also helps elucidate the potential role of re-irradiation with recurrent skull base meningiomas. In our cohort, there were no associated improvements in PFS with re-irradiation of grade 1 meningiomas. Conversely, the role of radiation seems to be more important for WHO 2 and WHO 3 meningiomas. Indeed, we found an improvement in PFS for re-irradiated WHO grade 2 meningiomas, but this finding is opposed to other authors 3 . Nevertheless, it is important to highlight that our patient cohort consisted exclusively of skull base meningiomas, which have a different genomic signature than convexity meningiomas and have different biological and clinical behavior 4 . Although survival and tumor control are poor in WHO grade 3 meningiomas, there is a consensus on the beneficial effect of radiation, irrespective of the EOR 5 , and in our cohort of anaplastic meningiomas, re-irradiation provided a PFS benefit when compared with surgery alone, demonstrating that salvage RT still has a survival impact in already radiated recurrences. Among demographic variables, age over 60 and KPS ≤ 70 were predictors of unfavorable results that have been seen in other studies 6 . To resume, we propose the following treatment algorithm according to our results and the literature reported (Figure 4).

• Treatment offered to recurrences Surgery alone (SX) was the most frequent treatment offered for recurrences in WHO grade 1 and WHO grade 2 patients (37% and 19.8%, respectively). Patients with GTR had a median time to recurrence of 123, 15 and 6 months for WHO grade 1, WHO grade 2 and WHO grade 3, respectively. Surgical procedures had a complication rate of 23.8% (20/84), and this rate increased over time: 10% (1/10), 18.4% (7/38), 100% (1/1), 39.3% (11/28) and 100% (1/1) for first, second, third, fourth and fifth surgeries, respectively. Re-irradiation therapy was administered for seventy-three recurrences. Re- irradiation was used along the course of the disease one, two and three time in 32 (66.7%), 13 (27%) and 3 patients (6.3%). Among them, 38 (52%) patients received EBRT, and 35 (48%) patients received SRS, with different doses . • Analysis of Factors Associated with PFS Upon conducting univariate log-rank and Cox proportional hazards analysis, we identified those variables that correlated with higher recurrence rate. Among demographics variables, the 3-year PFS was 43.5%, 24.5% and 0%, for WHO grade 1, WHO grade 2 and WHO grade 3, respectively (Figure 2, A). Furthermore, age ≥ 60 years-old was associated with increased progression (HR 1.68; 95% CI, 1.15-2.44; p=.0025) (Figure 2, B). As seen in Table 2, patients with WHO grade 1 meningiomas who underwent a STR had a 3.4- fold increase of disease progression compared to patients where GTR was achieved (HR 3.38; 95% CI, 1.268-9.03; p=.0189) (Figure 2, D). For WHO grade 2 and 3 patients however, EOR was not associated with differences in PFS (Figure 3, B and D). Furthermore, age ≥ 60 years-old was associated with increased progression (HR 1.68; 95% CI, 1.15-2.44; p=.0025) (Figure 2, B).

Figure 4. Diagram outlining proposed treatment algorithm for recurrent and radiated skull base meningiomas

References: 1) Abry E, Thomassen IØ, Salvesen ØO, Torp SH: The significance of Ki-67/MIB-1 labeling index in human meningiomas: a literature study. Pathology-Research and Practice 206:810-815, 2010 2) Aras S, Ozkanli S, Erdem E, Gokalp S, Meral G, Erdogan CE: Investigation of Low and High Dose Rate X-Ray Effects on Histopathological Changes and Prognostic Importance of Ki-67 In Laryngeal Cancer Radiotherapy. Available at SSRN 40372883) Porta et al. Pain Digest Pain Pain 1998;8:346-352 3) Momin AA, Shao J, Soni P, Almeida JP, Suh JH, Murphy ES, et al: Outcomes of salvage radiation for recurrent world health organization grade II meningiomas: a retrospective cohort study. Journal of Neuro-Oncology 152:373-382, 2021 4) Clark VE, Erson-Omay Ez Fau - Serin A, Serin A Fau - Yin J, Yin J Fau - Cotney J, Cotney J Fau - Ozduman K, Ozduman K Fau - Avşar T, et al: Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. 5) Goldbrunner R, Minniti G, Preusser M, Jenkinson MD, Sallabanda K, Houdart E, et al: EANO guidelines for the diagnosis and treatment of meningiomas, in, 2016, pp 383-383 6) Durand A, Labrousse F, Jouvet A, Bauchet L, Kalamaridès M, Menei P, et al: WHO grade II and III meningiomas: a study of prognostic factors. Journal of neuro-oncology 95: 367-375, 2009 Abbreviations: HR, Hazard ratio; PFS, progression free survival; EOR, extent of resection; GTR, gross total resection; STR, subtotal resection. Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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