Clinical necessity Re-radiotherapy for recurrent glioblastoma

Author: Zhao Yaowei

Beijing US-China Airui Cancer Hospital

Glioblastoma (GBM) is the most common malignant brain tumor
in adults.
Standard care includes surgery plus external beam radiation therapy (RT) with and maintenance of temozolomide, with a median reported survival (OS) of 14.
6 months and a 2-year OS rate of 26.
5 percent ^[1].

However, despite advances in surgery and chemoradiotherapy, almost all gliomas recur
within or adjacent to the initial site of onset.
There is currently no standard regimen for the treatment of relapse, which includes repeat surgery, re-irradiation, systemic therapy, and optimal supportive care ^[2].

Locally recurrent or progressive malignant gliomas with a median OS of six to 17 months can be treated surgically, and total or subtotal resection (resection > 80 percent of the resection range) is associated with longer OS ^[3,4]
.

About 90% of WHO grade IV gliomas (glioblastoma, GBM) will recur
locally within 2 years.
Due to the continuous advancement of radiation therapy technology, re-radiation therapy has become a viable treatment for
brain tumor patients.
Using stereotactic radiosurgery (SRS) or stereotactic radiation therapy (SRT), either hypofractionated or conventionally fractionated, several studies have shown a benefit in survival after re-irradiation in patients with relapsed GBM; However, questions remain to be answered
about the effectiveness and toxicity of second course of radiation therapy.

In patients with recurrent GBM, a second course of radiation therapy remains a concern, as the risk of neurotoxicity in the form of radiation necrosis is unacceptable
.
The key issue of GBM reirradiation is to accurately depict the target volume and risk organ (OAR) to accurately calculate the spatial dose distribution and select the optimal radiation dose segmentation protocol
.
Magnetic resonance imaging (MRI) is routinely used because it more accurately describes tumor extension and brain anatomy
than computed tomography (CT).
Positron emission tomography (PET)/CT imaging using radiolabeled amino acids may help improve the accuracy of target delineation by revealing tumor infiltration in areas with a nonspecific MRI appearance ^[5,6].

Normal brain tissue dose tolerance is a limiting factor
at reirradiation.
After SRS and SRT, radiation necrosis is a common complication
.
For conventional fractionation, a 5% and 10% risk of symptomatic radiation necrosis is expected to occur in each 2Gy fractionation pattern
at bioequivalent doses (BED) of 72 Gy (range, 60-84 Gy) and 90 Gy (range, 84-102 Gy).
In SRS, the risk of complications increases rapidly
once exposure to brain volume exceeding 5 to 10 mL at 12 Gy ^[7,8].
Several factors should be considered when assessing the risk of radiation necrosis after reirradiation, including dose and fractionation, amount of treatment, and interval
between combination chemotherapy and radiotherapy.
(EQD2) is calculated as the bioequivalent total dose (EQD2).

The estimated 1-year risk of radiation necrosis of cumulative EQD2 > 96.
2 Gy is 2-12%, and the risk of cumulative EQD2 > 137 Gy is up to 17%.

Niyazi et al^.
[9] showed no associated long-term toxicity
of 80.
3 Gy, 79.
4 Gy, and 95.
2 Gy for optic chiasm, optic nerve, and brainstem in 58 patients who underwent reirradiation for malignant glioma.

Appropriate patient selection is key
to improving clinical outcomes.
International guidelines recommend consideration of reirradiation with recurrent or progressive GBM in young patients with good performance status, particularly after prolonged radiation therapy ^[10,11].

SRS or high-dose fractionated SRT will be used for small targets of 5-15 ml, while segmented SRT using a 1.
8-2.
5 Gy fraction should be preferred for large tumors, especially if
located in structures close to the functional area.
In conclusion, re-irradiation has emerged as an effective and safe treatment option for selected patients with recurrent GBM
.
Using similar bioequivalent doses, different radiation techniques lead to similar survival outcomes
.
Treatment is associated
with a relatively low risk of toxicity when the appropriate radiation technique is carefully selected based on the size and location of the tumor and the recommended cumulative dose limit for the brain.

A patient treated by our hospital suffered from recurrence of glioblastoma after surgery complicated by herniation, and our department based on radiotherapy combined with bevacizumab and temozolomide, after re-radiotherapy and chemotherapy, the condition was significantly alleviated
.

 A yellow arrow indicates that the target is a tumor

Overall, re-irradiation therapy is an effective and safe treatment
for recurrent GBM.
Appropriately selected patients, whether SRS or SRT, whether low-fractionated or conventionally fractionated, are viable regimens with a median OS between 6 and 12 months and relatively low
toxicity.

Several studies have investigated the effects of re-irradiation in combination with systemic therapy, although its beneficial effect on survival remains controversial
.
Concomitant and/or adjuvant therapy with temozolomide prolongs overall and progression-free survival compared with radiotherapy alone, but this is usually limited to MGMT methylated tumors; In addition, other authors have not observed a significant survival advantage ^[12,13].

Several studies have shown that the addition of bevacizumab to SRS and fractionated SRT significantly prolongs OS compared with reirradiation alone ^[14,15]; In contrast, other studies have failed to demonstrate survival advantage
.

Overall, the different effects of chemoradiotherapy compared with radiotherapy alone on prognosis in patients with relapsed GBM remain to be determined
by prospective trials.
Another important issue that needs to be addressed is the potential advantages of synchronizing/adjuvant systemic therapy in combination with reirradiation, rather than systemic therapy
alone.

References: (Swipe up to view)

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Review: Jiang Zhou

Typesetting: Jiang Zhou

Execution: Small garden