Glioblastoma multiforme (GBM) is known for aggressive growth and a poor prognosis, even more so if the O6-methylguanine-DNA-methyltransferase (MGMT) promotor is unmethylated (median survival: 12.6 months; 5-yr survival: 8.3%) (1,2). Multidisciplinary treatment approaches have been established (1). However, given the challenging diagnosis, improving quality of life (QoL) during intensive therapy is another major challenge (3).
No clear consensus has been reached regarding the admissibility of physical exercise in GBM patients (4). However, clinically, patients are dissuaded from exercising, for instance in the German Cancer Society’s patient guidelines (5), mostly for fear of cancer-related events including epilepsy, intracranial bleeding, and accidents, such as falls (6,7), despite little supporting scientific evidence. This may limit patients’ everyday life and impact their QoL and thus necessitates investigation.
A review of rehabilitative and supportive care intervention trials (8) show that few studies investigate physical therapy in high-grade gliomas except for one case series (9) and individual cases (10,11) reporting well-tolerated moderate exercise regimens.
Here, we report a 20-month experience with high-intensity physical exercise, including marathon runs, in a GBM patient under continuous treatment.
The exercise intervention was approved by the institutional Ethics Committee. The patient provided written consent both for the exercise program and for an institutional newsletter report on his exercise. Additionally, his widow consented to this report.
In February 2015, a previously asymptomatic 33-yr-old male educator (182 cm, 90 kg, BMI: 27.2 kg·m−2) was admitted to our institution with increasing headaches and behavioral changes. Magnetic resonance imaging revealed a large 7.5 × 5.3 cm cystic tumor in the right frontal lobe with midline shift (Fig. 1A).
The patient underwent 95% resection of the basal ganglia-infiltrating mass (Fig. 1B). Glioblastoma multiforme was diagnosed with unmethylated MGMT, and without isocitrate dehydrogenase 1 or BRAF V600 mutations.
Postsurgery, the patient was readmitted for a week-long delirium while a single epileptic seizure was treated with levetiracetam (500 mg, 2 per day). The patient then underwent radiochemotherapy with temozolomide (75 mg·m−2) and 60 Gy of concurrent radiation (EORTC scheme) (12). Four weeks after chemoradiation, the patient started treatment with temozolomide (100 mg·d−1) while continuing antiepileptic therapy outside the university hospital.
Years before the GBM diagnosis, the patient had been a physically active, recreational runner, without formalized professional training. When diagnosed, he was overweight, in a depressed mood and showed little willingness to engage in exercise. During psycho-oncologic consultations, his wife supported the suggestion to restart physical exercise hoping to alleviate his mood fluctuations. Consequently, after chemoradiation and initial performance diagnostics that indicated he met the inclusion criteria (no severe neurologic deficits precluding patient participation, ability to grant informed consent, no refractory epileptic seizures (>3 focal seizures per day or >1 generalized seizure within 3 d of evaluation), and Eastern Cooperative Oncology Group score 0 or 1), the patient was included into the local Personal Training Program for neurooncological patients.
The program, established in 2011, consists of two monitored weekly sessions with a dedicated and certified personal coach, one focusing on bicycle exercise and dumbbell workout with the other training coordination and running. Patient well-being, including mood, pain, and adverse events were monitored at least weekly by the certified coach. Monitored training sessions were complemented with at least two weekly sessions of individual home training. Training intensity was 70% to 75% of the age-dependent maximum heart rate (MHR) (13).
A Polar V 800 sports watch (Polar Electro, Kempele, Finland) allowed recording of exercise type, time, and intensity. Training intensity was measured in metabolic equivalent of task hours (MET·h) per week. The equivalent of 1 MET·h of exercise is the amount of energy spent for 1 h while at rest.
In this setting, the patient established continuous high-intensity training including running, cycling, walking, power training, soccer, swimming, and even skiing.
In April 2016, after several shorter running competitions, the patient concluded a marathon in 3 h 30 min (4:59 min·km−1) despite a relapse (Fig. 1C) and days before surgery. At the time, additional performance diagnostics indicated improved fitness compared with training onset.
One week after uneventful recraniotomy, the patient was eager to resume exercise while under alternate therapy with lomustine (CCNU). Despite surgical success, a second relapse was diagnosed 2 months later (Fig. 1D) and, again, removed operatively. Afterwards, reradiation (39.6 Gy) and a bevacizumab therapy were initiated while the patient restarted training of his own accord. Maximum exercise intensity of nearly 100 MET·h·wk−1 was reached in September 2016, 1 wk before another marathon. Despite additional therapy, the patient again improved both in marathon time (3 h 17 min, 4:40 min·km−1) and performance diagnostics.
In December 2016, a third relapse occurred. Four weeks later, increasing intracranial pressure caused by multiple intraventricular lesions (Fig. 1E) led to the implantation of a ventriculoperitoneal shunt and a treatment change to CCNU and hydroxyurea. However, pressure-related symptoms, including vomiting, intermittent phases of somnolence, and nystagmus with impaired vision never remitted entirely. In February 2017, after close discussion with the patient and his family and given progressing symptoms, including cranial nerve deficits, the patient was transferred to a hospice. Two weeks later, he passed away, 2 yr and 4 d after initial diagnosis.
The patient had continued his exercise training of his volition until 6 wk before his death (timeline in Fig. 2; see Figure, Supplemental Digital Content 1: Number of monthly exercise sessions spent on different training modalities between May 2015 and January 2017, http://links.lww.com/MSS/B653; and see Figure, Supplemental Digital Content 2: time in hours of monthly exercise spent on different training modalities between May 2015 and January 2017, http://links.lww.com/MSS/B654). Over the course of 87 continuous weeks, from May 2015 to January 2017, documented physical training equaled 3804 MET·h averaging 43.7 MET·h·wk−1, despite multiple regimens of surgery, radiation, and chemotherapy. Over time, the patient improved in performance diagnostics (Fig. 3). During this entire period, the patient did not encounter any adverse events including accidents or epileptic seizures and had good QoL.
Glioblastoma is among the most aggressive malignancies, with a strongly unfavorable prognosis, even more so with unmethylated MGMT promotor, as in this case (14,15). Integrated therapy is crucial in patients diagnosed with GBM (3). However, physical exercise is rarely offered to patients and thus remains a somewhat unknown factor (16):
A previous case series evaluated a training program both significantly shorter (12 wk vs 89 wk) and of lower intensity (one coordinated weekly training plus two sessions at home vs at least two plus two) compared with this study (9). The findings from this previous investigation (improved fitness and QoL) are in line with those in this present study. However, in the case series, only seven of 24 participants were GBM patients, only four of them finished the 12-wk program and only one third of all patients (and an unknown number of GBM patients) were under treatment during the intervention.
Another case study included one GBM patient under no therapy except for bevacizumab (10). The intervention again lasted only 12 wk and was of similar intensity as the case series.
A third case report included a 6-wk training regimen in a GBM patient totaling 15 exercise sessions only. Again, functional outcome and QoL were improved (11), as in this present study.
This study provides the most high-intensity and long-time exercise regimen reported to date in a GBM patient and may help to establish several conclusions:
Physical exercise programs are feasible, even during radiation and/or chemotherapy, and postoperatively
The exercise program in this presented case was extensive, even in comparison to guidelines for healthy adults.
With 43.7 MET·h·wk−1, the patient quadrupled high-intensity thresholds of 6 to 10 MET·h·wk−1 for healthy populations and even surpassed the 75th percentile of male volunteers averaging 37.4 MET·h·wk−1 (17).
Thus, despite constant treatment including surgery, radiation and chemotherapy, the patient was able to adhere to a high-level exercise program with multiple training sessions per week. Although we would not generally recommend a similarly intensive training schedule to all GBM patients, this serves as a strong example that supervised exercise, even if time-consuming and of high intensity, can be well combined with multidisciplinary GBM therapy.
Well-planned exercise programs facilitate long-term patient adherence to the training
Originally, the patient did not show a strong willingness to engage in physical training. He was overweight, slightly slowed down in movement and thought process due to his disease and in a depressed mood. In his case, a deciding factor was his wife who encouraged his exercise. However, with increasing training and fitness, the patient’s own motivation to continue his exercise grew. Additionally, several external factors may also have contributed to his training adherence: The individual one-on-one training allowed the patient to exercise at his own pace. The interaction with the personal coach helped the patient gain trust in his abilities which encouraged him to increase training intensity. Lastly, the training took place outside the hospital in a professional exercise setting where the patient was primarily addressed as an athlete, and not as a patient. Although further study is needed, we believe that these factors are key to ensuring the patients’ well-being and a training program’s success.
A gain of physical fitness is possible despite multimodal GBM therapy
As illustrated by performance diagnostics, the patient’s fitness increased by 33% relative to body weight between May 2015 and October 2016, despite multiple surgeries, chemotherapies, and radiation therapy regimens. Healthy individuals of the patient’s age reach 75% of MHR at 1.58 W·kg−1 (13). At the onset of training, the patient surpassed this threshold by 27%; in October 2016, he nearly doubled it. Although oncologic patients commonly lose fitness over the course of their disease (18), this case study suggests that intensive exercise may potentially reverse this trend in this patient population.
The high-intensity physical exercise program did not produce any adverse events
Although single cases do not allow generalizable safety conclusions, it is striking that—despite high-intensity long-time training, including marathon runs—no adverse events were encountered. Of note, the only epileptic seizure occurred before training onset and did not recur despite tumor progression. This study of extraordinary training is well suited to encourage further studies in the field and may alleviate fear of negative events. It underlines that GBM patients can be encouraged to be physically active in a monitored setting.
Studies investigating physical exercise in terms of QoL and overall survival are warranted
It is known that a good performance status according to the Eastern Cooperative Oncology Group is independently associated with prolonged survival (19). In our case, the patient gained fitness through exercise, voluntarily expanding his training. According to his family, physical exercise significantly improved his mood, well-being, and QoL at large.
Current studies indicate that 2-yr survival in GBM patients with unmethylated MGMT is 15% (12,20). Despite large GBM tumor size at time of diagnosis and incomplete resection, survival in our patient surpassed the median considerably. Although this does not allow general deductions linking physical exercise to overall survival, it certainly underlines the need for further study.
In the present study, high-intensity exercise was successfully implemented in a GBM patient despite continuous multidisciplinary treatment. Although the extraordinary level of physical exercise presented in this case is certainly testament to the patient’s individual level of commitment and exercise, this study sheds light on the broader discussion surrounding physical activity in glioblastoma patients.
The authors received no specific funding for this work.
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this article.
The results of this study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute endorsement by ACSM.
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GLIOBLASTOMA MULTIFORME; FITNESS; SUPPORTIVE CARE; QUALITY OF LIFE
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