Abstract
Aim: There is little consensus on salvage management of glioblastoma after recurrence, for lack of evidence.
Materials & methods: A retrospective study of treatments in patients with recurrent glioblastoma.
Results: Surgery at recurrence was related to better overall survival (OS) and progression-free survival (PFS). Surgery at recurrence, Karnofsky index, MGMT methylation status, younger age at diagnosis and number of chemotherapy cycles were positive factors for OS and PFS. The benefit of OS was relevant for a second surgery performed at least 9 months after the first one. Systemic treatments after the second surgery were linked to an improved PFS.
Conclusion: Younger age, Karnofsky index, MGMT methylation status and a median time between surgeries ≥9 months may be criteria for eligibility for surgery at recurrence.
Keywords: : Age, glioblastoma, Karnofsky index, MGMT methylation status, prognostic criteria, recurrence, recurrence delay, second surgery, survival
Plain language summary
Article highlights.
Therapeutic options for the recurrence of glioblastoma are scarce.
There are no shared recommendations for the treatment of recurrent glioblastoma.
We made a retrospective study on patients with recurrent glioblastoma, comparing those who had a second surgery vs those who had other treatments.
Second surgery was related to better overall survival (OS) and progression-free survival (PFS).
Second surgery, Karnofsky index, MGMT methylation status, younger age at diagnosis and number of chemotherapy cycles were positive factors for OS and PFS.
The benefit of OS was relevant for a second surgery performed at least 9 months after the first one.
Systemic treatments after the second surgery were linked to an improved PFS.
Second surgery is the first-line intervention choice at recurrence in a selected subset of patients.
The surgery option should be part of a multidisciplinary diagnostic and therapeutic pathway.
1. Background
Glioblastoma accounts for 30% of CNS tumors [1]. The standard of care for newly diagnosed glioblastoma has been maximally safe resection, radiotherapy (RT) and concurrent and adjuvant temozolomide for over 15 years. However, treated patients have a poor prognosis, with a median overall survival (OS) of 15 months and recurrence within a median time of 7 months [2–4].
Upon recurrence, there is little consensus on salvage management [4]. Although current international guidelines state that repeated resection may be suitable for selected candidates, limited evidence exists on the appropriate criteria for such selection [5–7]. Indeed, available data are drawn from retrospective studies carried out in heterogeneous populations with different end points and are difficult to compare [8–11]. Additionally, these studies did not rule out differences in tumor- and surgery-associated factors.
To address this lack of evidence, as randomized controlled studies are difficult in this population, several studies have been carried out in a real-life setting and published in the past 3 years. Overall, researchers still agree that surgery for recurrent glioblastoma can be beneficial in selected patients and is associated with an acceptable morbidity rate [3,12–15]. Nevertheless, the heterogeneity of the patients and the persistence of variable surgical expertise and instrumentation hamper definite conclusions, and further studies are needed to identify patient eligibility criteria.
With the aim to shed light on this topic, we retrospectively analyzed data on patients with recurrent glioblastoma who underwent either a second surgery or other therapies in two centers in Italy. We investigated whether second surgery was beneficial in our patients and whether a subset of patients with a high probability of benefit could be identified.
2. Materials & methods
2.1. Study design
A retrospective study was carried out in IRCCS Regina Elena National Cancer Institute, Rome, Italy and Neuro-Oncology Unit, Fondazione IRCSS Istituto Neurologico Carlo Besta, Milan, Italy, between January 2004 and December 2022.
2.2. Study population
The study enrolled consecutive patients with histological diagnosis of glioblastoma (according to WHO criteria) who had recurrent disease.
2.3. Data sources
Demographic and clinical data were obtained from clinical records. The following clinical variables were extracted from our databases: Karnofsky index after chemotherapy prior to recurrence, MGMT methylation status, the number of chemotherapy cycles before recurrence (CT1), the time elapsed from the first to the second surgery, and treatments after the second surgery. The Karnofsky index criteria are: able to carry on normal activity and to work; no special care needed; unable to work; able to live at home and care for most personal needs; varying amount of assistance needed; unable to care for self; requires equivalent of institutional or hospital care; and disease may be progressing rapidly [16]. The patients were stratified into a group that received a second surgery and a group that received other therapies or no therapy after recurrence.
2.4. Outcomes
The end points were OS (defined as the time from the first surgery to death or loss to follow-up, whichever occurred first), progression-free survival (PFS) after the first surgery (defined as the time from the first surgery to documented radiological progression, death or loss to follow-up, whichever occurred first) and PFS2 (defined as the time from the second surgery to documented radiological progression, death or loss to follow-up, whichever occurred first).
2.5. Procedures
Patients with recurrent disease were discussed in a multidisciplinary tumor team in both centers.
2.6. Ethics committee approval
According to the current regulation of observational studies, the study was notified to the ethics committee of IRCCS Regina Elena National Cancer Institute, Rome, Italy (Comitato Etico Territoriale Lazio Area 5 – Roma, Italy; protocol IFO_058.IFO_AOO; 14 September 2023). The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.
2.7. Patient consent
Patients released informed consent to surgery and to the publication of anonymous data.
2.8. Statistical analysis
Demographic and clinical data were summarized using descriptive statistics. Potential differences between groups were tested with the Chi-square or Mann–Whitney tests for categorical and continuous variables, respectively. Survival analyses were carried out using the Kaplan–Meier method, and the log-rank test evaluated differences between the curves. The hazard ratios (HRs) and the relative 95% CIs were estimated using the Cox proportional-hazards regression model. Multivariate models were built with variables that resulted in significant univariate analysis. A p-value of <0.05 was considered statistically significant. All analyses were carried out with SPSS (IBM) v.28.
3. Results
3.1. Patients description
A total of 560 patients were included, of whom 219 were female, ranging in age at diagnosis from 16 to 85 years (Table 1).
Table 1.
Patient characteristics of all included patients (n = 560).
| Patient characteristics | Second surgery | p-value | |
|---|---|---|---|
| Yes, n (%) | No, n (%) | ||
| Total | 138 (25) | 422 (75) | |
| Gender: | 0.070† | ||
| Female | 63 (46) | 156 (37) | |
| Male | 75 (54) | 266 (63) | |
| Age at diagnosis (years), median (min-max) | 56 (23–80) | 61 (16–85) | <0.001‡ |
| MGMT: | 0.673† | ||
| Methylated | 51 (49) | 131 (47) | |
| Not methylated | 53 (51) | 150 (53) | |
| Number of CT1 cycles, median (min-max) | 8 (1–42) | 6 (1–40) | |
| Time to second surgery from first surgery: | |||
| <12 months | 68 (49) | ||
| >12 months | 70 (51) | ||
| Median (min-max) | 13 (0–129) | ||
| Treatment post second surgery: | |||
| None | 26 (19) | ||
| RT-CT | 22 (16) | ||
| Only CT (1 or 1+ cycles) | 90 (65) | ||
Chi-square test.
Mann–Whitney U test.
CT: Chemotherapy; RT: Radiotherapy.
The second surgery was performed in 138 (25%) patients, while in 422 (75%), radiotherapy and chemotherapy (RT + CT), CT alone or supportive care were performed. Among the 422 patients who did not receive second surgery, 242 (57%) underwent supportive therapies, and 180 (43%) underwent active treatments (RT + CT or CT alone). The two groups were not significantly different in female-to-male ratio and MGMT methylation status frequency, while patients who received a second surgery were significantly younger than patients in the other group (median age at diagnosis 56 vs 61 years; p < 0.001) and had received a higher median number of CT cycles (8 vs 6; p < 0.001).
After the second surgery, 26 (19%) patients received supportive care, 22 (16%) received RT + CT (RT followed by CT) and 90 (65%) received only CT.
3.2. Oncological outcomes
3.2.1. OS
The median OS (±standard error) was 18 ± 0.58 months (95% CI: 16.8–19.1) in the entire study population, 25 ± 2.07 months (95% CI: 20.9–29.0) in patients treated with a second surgery and 15 ± 0.56 months (95% CI: 13.9–16.0) in those who did not undergo a second surgery, with a significant difference between the two subgroups (p < 0.0001; Figure 1). The patients who underwent a second surgery more than 12 months after the first intervention had a better OS than those who had a second surgery ≤12 months after the first one (median OS: 38 ± 4.97 months, 95% CI: 28.2–47.7 vs OS: 18 ± 0.77 months, 95% CI: 16.4–19.5; p < 0.001; Figure 2). A difference in OS was also found between those who had a second surgery more than 9 months after the first intervention and those who had a second surgery ≤9 months after the first one (median OS: 30 ± 2.21 months, 95% CI: 25.6–34.3 vs median OS: 18 ± 0.92 months, 95% CI: 16.1–19.8; p < 0.001); no significant difference was found for a cut-off of 6 months (p = 0.09; Supplementary Figure S1).
Figure 1.
Overall survival in patients undergoing and not undergoing a second surgery.
Figure 2.
Overall survival of patients undergoing a second surgery either within 12 months or after ≥12 months from the first intervention.
The OS of patients who underwent a second surgery was not related to the subsequent systemic treatment. The median OS of patients who had no systemic therapy was 26 ± 2.90 months (95% CI: 20.3–31.6), of those who had RT + CT was 24 ± 1.69 months (95% CI: 20.6–27.3), and of those who had only CT was 27 ± 3.01 months (95% CI: 21.0–32.9), with a not significant difference (p = 0.95). No significant difference in OS was also observed when the treatment groups were compared.
3.2.2. Cox proportional hazard models
We tested, as potential factors that could impact OS and PFS, gender, age at diagnosis, the time to second surgery (≤12 months vs >12 months), MGMT methylation status, the Karnofsky index, a higher number of previous CT1 cycles and the type of treatment after the second surgery.
The multivariate analysis, built with variables that resulted significantly from univariate analysis, of the whole population showed that the second surgery, a higher Karnofsky index, MGMT methylation status, younger age at diagnosis and a higher number of previous CT1 cycles were factors associated with a longer survival (Table 2). Among patients undergoing a second surgery, multivariate analysis showed that MGMT methylation status, a higher Karnofsky index, a higher number of previous CT1 cycles and time to second surgery were factors associated with longer survival (Table 3).
Table 2.
Univariate and multivariate analysis for overall survival in the whole population (n = 560).
| Parameter | Comparison | Univariate | Multivariate (forward) | ||
|---|---|---|---|---|---|
| HR (95% CI) | p-value | HR (95% CI) | p-value | ||
| Second surgery | No vs yes | 1.91 (1.54–2.36) | <0.001 | ||
| Karnofsky after CT1 status | Continuous | 0.97 (0.96–0.97) | <0.001 | 0.97 (0.97–0.98) | <0.001 |
| MGMT methylation status | Yes vs no | 0.55 (0.43–0.69) | <0.001 | 0.51 (0.39–0.66) | <0.001 |
| Gender | Male vs female | 1.03 (0.85–1.25) | 0.755 | ||
| Age at diagnosis | Continuous | 1.03 (1.02–1.04) | <0.001 | 1.02 (1.01–1.03) | <0.001 |
| Number of CT1 cycles | Continuous | 0.91 (0.89–0.93) | <0.001 | 0.92 (0.90–0.95) | <0.001 |
CT: Chemotherapy; HR: Hazard ratio.
Table 3.
Univariate and multivariate analysis of factors associated with overall survival in patients undergoing a second surgery (n = 138).
| Parameter | Comparison | Univariate | Multivariate (forward) | ||
|---|---|---|---|---|---|
| HR (95% CI) | p-value | HR (95% CI) | p-value | ||
| Time to second surgery | ≤12 months vs >12 months | 3.37 (2.29–4.95) | <0.001 | 2.46 (1.53–3.97) | <0.001 |
| Karnofsky after CT1 status | Continuous | 0.97 (0.96–0.99) | <0.001 | 0.97 (0.95–0.99) | <0.001 |
| MGMT methylation status | Yes vs no | 0.43 (0.28–0.66) | <0.001 | 0.56 (0.35–0.89) | 0.015 |
| Gender | Male vs female | 0.83 (0.57–1.20) | 0.314 | ||
| Age at diagnosis | Continuous | 1.01 (0.99–1.03) | 0.150 | ||
| Number of CT1 cycles | Continuous | 0.93 (0.90–0.97) | <0.001 | 0.95 (0.91–0.99) | 0.031 |
| Treatment post-second surgery | RT + CT vs none | 1.01 (0.54–1.89) | 0.968 | ||
| CT vs none | 0.95 (0.58–1.54) | 0.830 | |||
CT: Chemotherapy; HR: Hazard ratio; RT: Radiotherapy.
Regarding the PFS, the second surgery, MGMT methylation status, a higher Karnofsky index and a higher number of previous CT1 cycles were factors associated with a longer time previous disease relapse in the whole sample (Table 4).
Table 4.
Univariate and multivariate analysis for progression-free survival in the whole population (n = 560).
| Parameter | Comparison | Univariate | Multivariate (forward) | ||
|---|---|---|---|---|---|
| HR (95% CI) | p-value | HR (95% CI) | p-value | ||
| Second surgery | No vs yes | 1.96 (1.58–2.44) | <0.001 | 1.81 (1.37–2.39) | <0.001 |
| Karnofsky after CT1 status | Continuous | 0.98 (0.97–0.98) | <0.001 | 0.99 (0.98–0.99) | <0.001 |
| MGMT methylation status | Yes vs no | 0.58 (0.46–0.73) | <0.001 | 0.76 (0.60–0.98) | 0.032 |
| Gender | Male vs female | 1.16 (0.95–1.43) | 0.155 | ||
| Age at diagnosis | Continuous | 1.02 (1.01–1.03) | <0.001 | ||
| Number of CT1 cycles | Continuous | 0.89 (0.87–0.91) | <0.001 | 0.88 (0.85–0.91) | <0.001 |
CT: Chemotherapy; HR: Hazard ratio.
3.2.3. PFS from the second surgery
The median PFS2 in the whole group with a second surgery was 5 ± 0.54 months (95% CI: 3.9–6.0). PFS2 was not significantly different in patients who had a second surgery within 12 months after the first intervention and those who had a second surgery ≥12 months after the first one (HR: 1.18; 95% CI: 0.83–1.68; p = 0.357). PFS2 was significantly different according to the systemic treatment after surgery (p < 0.0001). The median PFS2 was 1 ± 0 months for those who received no systemic treatment, 9 ± 0.74 months (95% CI: 7.5–10.4) for those who received RT + CT, and 6 ± 0.48 (95% CI: 5.0–6.9) for those who received only CT. The patients not receiving systemic therapy had worse PFS2 than those receiving RT + CT (p = 0.04) and those receiving only CT (p < 0.0001). There was no significant difference in PFS2 between the groups with RT + CT and CT alone (p = 0.13).
In the subgroup of patients who underwent a second surgery, factors related to PFS in multivariate models were: MGMT methylation status (p = 0.008), a higher Karnofsky index (p = 0.018) and a higher number of previous CT1 cycles (p < 0.001; Table 5). Only 3/138 (2.1%) patients had postsurgical complications.
Table 5.
Univariate and multivariate analysis of factors associated with progression-free survival in patients undergoing a second surgery (n = 138).
| Parameter | Comparison | Univariate | Multivariate (forward) | ||
|---|---|---|---|---|---|
| HR (95% CI) | p-value | HR (95% CI) | p-value | ||
| MGMT methylation status | Yes vs no | 0.49 (0.33–0.73) | <0.001 | 0.56 (0.36–0.86) | 0.008 |
| Karnofsky after CT1 status | Continuous | 0.98 (0.97–0.99) | 0.003 | 0.98 (0.96–0.99) | 0.018 |
| Gender | Male vs female | 1.19 (0.84–1.69) | 0.316 | ||
| Age at diagnosis | Continuous | 1.01 (0.99–1.02) | 0.320 | ||
| Number of CT1 cycles | Continuous | 0.92 (0.89–0.95) | <0.001 | 0.93 (0.89–0.97) | <0.001 |
| Treatment post-second surgery | RT + CT vs none | 0.86 (0.48–1.56) | 0.630 | ||
| CT vs none | 0.93 (0.60–1.45) | 0.758 | |||
CT: Chemotherapy; HR: Hazard ratio; RT: Radiotherapy.
4. Discussion
4.1. Key results
This retrospective multicentric study of patients with recurrent glioblastoma investigated the outcomes of a second surgery compared with a wide control group not receiving a second surgery.
It showed that the patients who underwent a second surgery had better OS and PFS2 than those who did not receive this treatment. Indeed, a second surgery, Karnofsky index, MGMT methylation status, younger age at diagnosis and the number of CT1 cycles were positive factors for OS and PFS, in agreement with previous findings [17].
4.2. Interpretation
The role of repeat surgery in patients with progressive or recurrent glioblastoma remains controversial. Some retrospective studies proposed a survival benefit after reoperation [18–21], while others did not [22].
In literature, favorable prognostic factors in the glioblastoma sample are young age, radical resection, satisfactory general condition of the patient MGMT promoter methylation and IDH mutations gene [23]. In our study, the benefit of a second intervention seemed relevant for those who had undergone surgery at least 9 months after the first one.
Tumor recurrence is nearly universal in glioblastoma, but today, evidence-based guidelines for treatment decisions upon disease recurrence are lacking [24]. This study confirms that most patients undergo second-line treatment, and only a small percentage undergo neurosurgery.
A prospective registry study of 764 patients with glioblastoma reported that only a third of patients reoperated at recurrence did not suggest a benefit [25]. In contrast, in a meta-analysis of eight prospective phase I and II trials comprising 300 patients with recurrent glioblastoma, second surgery was not an independent predictor for PFS and OS [26].
In our case series, factors toward eligibility confirmed that the second surgery is offered to subjects with better general health and slower tumors in the real-life setting. Different criteria were adopted in other groups, resulting in a different proportion of patients receiving second surgery. Ening et al. reported that 38% of patients with glioblastoma had a second intervention, and the most frequent indications had been maximum possible tumor resection mass reduction and symptom relief [27].
Brem et al. showed that preoperative performance status and age were significant prognostic factors [28], while, in another study, only performance status was found to be a significant predictor of outcome [29].
The extent of initial resection has also been shown to influence patient survival [30]. The general consensus is that resection should be seriously considered in those with a high Karnofsky performance status score (>70) and whose lesions are in a favorable location. Wann et al. showed that postoperative functional impairment after repeated surgery was not significantly different from that of their case controls [31]. Although there is no significant evidence to suggest the contrary, more rigorous evaluation in prospect will allow for a better understanding and interpretation of quality of life metrics in ascertaining the role of repeated surgery in recurrent glioblastoma.
MGMT methylation was associated with OS but not with PFS2 after the second surgery. Previous studies did not report any correlation between MGMT methylation status and indication for a second intervention [32], nor the outcomes of a second surgery [33].
Our low rate of complications after the second surgery may result from selecting patients in good general condition and with reduced surgical risk. This observation suggests the importance of identifying selection criteria for reintervention of recurrent patients.
Systemic treatments following the second surgery were linked to an improved PFS2 but not with OS, further suggesting that repeated intervention may be an independent factor for prolonged survival.
When faced with evidence of recurrent glioblastoma, surgical intervention requires clear identification of short-term goals and a diligent consideration of the overall prognosis. Surgery can improve neurological status and possibly increase the efficacy of adjunctive therapy.
Second surgery can represent a relevant therapeutic option in a selected subgroup of patients in order to avoid post-surgery complications and the deterioration of quality of life that could preclude further systemic treatments.
Although our results cannot be used to build a decisional algorithm for a second surgery after glioblastoma recurrence, they confirm that younger age, Karnofsky index, MGMT methylation status and a median time from the first surgery to progression ≥9 months and the possibility of other systemic treatment after surgery may be reliable criteria for the selection of patients who have a better chance of benefit, with low risk of complications.
4.3. Limitations
A limitation of our study is the retrospective design, while its strength is the large control group.
5. Conclusion
In our study, the second surgery represents the first-line intervention choice at recurrence in a selected subset of the sample. Factors to be considered in patient selection are: younger age, a higher number of CT cycles, MGMT methylation and, overall, a time to second surgery longer than 9 months. The surgery option should be part of a multidisciplinary diagnostic and therapeutic pathway aiming at evaluating benefits and risks. A second surgery should be considered if further therapeutic options are available for the follow-up.
Supplementary Material
Acknowledgments
Editorial assistance was provided by L Brogelli, A Shah and V Attanasio (Polistudium Srl, Milan, Italy). This activity was supported by internal funds.
Supplemental material
Supplemental data for this article can be accessed at https://doi.org/10.1080/14796694.2024.2358743
Author contributions
Study conception and design: M Lecce, F Rasile; collection and interpretation of data: F Rasile; V Villani, A Pace; P Gaviani; C Mariantonia, BCM Novello; statistical analysis: I Terrenato; manuscript drafting: M Lecce, F Rasile; A Tanzilli manuscript editing: S Telera, M Lecce; approval to submit, M Lecce.
Financial disclosure
The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing disclosure
Medical writing support was provided by Laura Brogelli, PhD, Aashni Shah and Valentina Attanasio (Polistudium Srl, Milan, Italy) and was supported by internal funds.
Funding
The study was supported by internal funds.
Ethical conduct of research
All patients included were treated in IRCCS Regina Elena National Cancer Institute, Rome, Italy and Neuro-Oncology Unit, Fondazione IRCSS Istituto Neurologico Carlo Besta, Milan, Italy, between January 2004 and December 2022. The present study was notified to the Ethics Committee of IRCCS Regina Elena National Cancer Institute, Roma, Italy (Comitato Etico Territoriale Lazio Area 5 – Roma, Italy; protocol IFO_058.IFO_AOO; 14 September 2023). Participants released informed consent to surgery. The study was conducted in accordance with the ethical principles of the 1964 Declaration of Helsinki and its later amendments.
Data availability statement
All data are available from the corresponding author upon reasonable request.
Consent to participate
Participants released informed consent to surgery, to inclusion in the study, and to publication of anonymous data.
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Data Availability Statement
All data are available from the corresponding author upon reasonable request.