Pattern of Failure After Limited Margin Radiotherapy and Temozolomide for Glioblastoma

Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, USA.
International journal of radiation oncology, biology, physics (Impact Factor: 4.26). 01/2011; 79(1):130-6. DOI: 10.1016/j.ijrobp.2009.10.048
Source: PubMed


To evaluate the pattern of failure after limited margin radiotherapy for glioblastoma.
We analyzed 62 consecutive patients with newly diagnosed glioblastoma treated between 2006 and 2008 with standard fractionation to a total dose of 60 Gy with concurrent temozolomide (97%) or arsenic trioxide (3%). The initial clinical target volume included postoperative T2 abnormality with a median margin of 0.7 cm. The boost clinical target volume included residual T1-enhancing tumor and resection cavity with a median margin of 0.5 cm. Planning target volumes added a 0.3- or 0.5-cm margin to clinical target volumes. The total boost planning target volume (PTV(boost)) margin was 1cm or less in 92% of patients. The volume of recurrent tumor (new T1 enhancement) was categorized by the percent within the 60-Gy isodose line as central (>95%), infield (81-95%), marginal (20-80%), or distant (<20%). For comparison, an initial planning target volume with a 2-cm margin and PTV(boost) with a 2.5-cm margin were created for each patient.
With a median follow-up of 12 months, radiographic tumor progression developed in 43 of 62 patients. Imaging was available for analysis in 41: 38 (93%) had central or infield failure, 2 (5%) had marginal failure, and 1 (2%) had distant failure relative to the 60-Gy isodose line. The treated PTV(boost) (median, 140 cm(3)) was, on average, 70% less than the PTV(boost) with a 2.5-cm margin (median, 477 cm(3)) (p < 0.001).
A PTV(boost) margin of 1cm or less did not appear to increase the risk of marginal and/or distant tumor failures compared with other published series. With careful radiation planning and delivery, it appears that treatment margins for glioblastoma can be reduced.

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    • "Emory University published their experience with 43 patients with disease progression after treatment with concurrent temozolomide and radiation with 0.5 cm CTV margins [15]. They found that 93% of patients recurred within the treatment field, 5% were marginal, and 2% were distant relative to the 60 Gy isodose line. "
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    ABSTRACT: Background To analyze patterns of failure in patients with glioblastoma multiforme (GBM) treated with limited-margin radiation therapy and concurrent temozolomide. We hypothesize that patients treated with margins in accordance with Adult Brain Tumor Consortium guidelines (ABTC) will demonstrate patterns of failure consistent with previous series of patients treated with 2–3 cm margins. Methods A retrospective review was performed of patients treated at the University of Alabama at Birmingham for GBM between 2000 and 2011. Ninety-five patients with biopsy-proven disease and documented disease progression after treatment were analyzed. The initial planning target volume includes the T1-enhancing tumor and surrounding edema plus a 1 cm margin. The boost planning target volume includes the T1-enhancing tumor plus a 1 cm margin. The tumors were classified as in-field, marginal, or distant if greater than 80%, 20-80%, or less than 20% of the recurrent volume fell within the 95% isodose line, respectively. Results The median progression-free survival from the time of diagnosis to documented failure was 8 months (range 3–46). Of the 95 documented recurrences, 77 patients (81%) had an in-field component of treatment failure, 6 (6%) had a marginal component, and 27 (28%) had a distant component. Sixty-three patients (66%) demonstrated in-field only recurrence. Conclusions The low rate of marginal recurrence suggests that wider margins would have little impact on the pattern of failure, validating the use of limited margins in accordance ABTC guidelines.
    Full-text · Article · Jun 2014 · Radiation Oncology
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    • "At our institution, we have previously reported the use of reduced margin radiotherapy in the management of GBM patients [36]. McDonald et al. found that use of total PTV margins of less than 1 cm resulted in radiographic tumor progression rates comparable with standard 2.3 cm to 2.5 cm GBM PTV margins. "
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    ABSTRACT: To dosimetrically evaluate the effect of reduced margin radiotherapy on hippocampal dose for glioblastoma multiforme (GBM) patients. GBM patients enrolled on the Radiation Therapy Oncology Group (RTOG) 0825 trial at our institution were identified. Standard RTOG 0825 expansions were 2 cm + 3-5 mm from the gross tumor volume (GTV) to the clinical tumor volume (CTV) and from the CTV to the planning tumor volume (PTV), respectively. These same patients also had reduced margin tumor volumes generated with 8 mm (GTV to CTV) + 3 mm (CTV to PTV) expansions. Individual plans were created for both standard and reduced margin structures. The dose-volume histograms were statistically compared with a paired, two-tailed Student's t-test with a significance level of p < 0.05. A total of 16 patients were enrolled on RTOG 0825. The reduced margins resulted in statistically significant reductions in hippocampal dose at all evaluated endpoints. The hippocampal Dmax was reduced from a mean of 61.4 Gy to 56.1 Gy (8.7%), D40% was reduced from 49.9 Gy to 36.5 Gy (26.9%), D60% was reduced from 32.7 Gy to 18.7 Gy (42.9%) and the D80% was reduced from 27.3 Gy to 15.3 Gy (44%). The use of reduced margin PTV expansions in the treatment of GBM patients results in significant reductions in hippocampal dose. Though the exact clinical benefit of this reduction is currently unclear, this study does provide support for a future prospective trial evaluating the neurocognitive benefits of reduced margin tumor volumes in the treatment of GBM patients.
    Full-text · Article · Jan 2014 · Radiation Oncology
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    • "Radiotherapy is an important component of the treatment of glioblastoma multiforme (GBM), but despite the high radiation doses used and the combination of anticancer agents and targeted therapies, the tumors invariably recur, leading to the demise of more than 75% of the patients by 2 years. Importantly, most of the recurrences occur within the radiation field.1–4 Thus any method of improving local control of the primary tumor would improve the curability of GBM patients. "
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    ABSTRACT: Background Tumor irradiation blocks local angiogenesis, forcing any recurrent tumor to form new vessels from circulating cells. We have previously demonstrated that the post-irradiation recurrence of human glioblastomas in the brains of nude mice can be delayed or prevented by inhibiting circulating blood vessel-forming cells by blocking the interaction of CXCR4 with its ligand stromal cell-derived factor (SDF)-1 (CXCL12). In the present study we test this strategy by directly neutralizing SDF-1 in a clinically relevant model using autochthonous brain tumors in immune competent hosts.Methods We used NOX-A12, an l-enantiomeric RNA oligonucleotide that binds and inhibits SDF-1 with high affinity. We tested the effect of this inhibitor on the response to irradiation of brain tumors in rat induced by n-ethyl-N-nitrosourea.ResultsRats treated in utero with N-ethyl-N-nitrosourea began to die of brain tumors from approximately 120 days of age. We delivered a single dose of whole brain irradiation (20 Gy) on day 115 of age, began treatment with NOX-A12 immediately following irradiation, and continued with either 5 or 20 mg/kg for 4 or 8 weeks, doses and times equivalent to well-tolerated human exposures. We found a marked prolongation of rat life span that was dependent on both drug dose and duration of treatment. In addition we treated tumors only when they were visible by MRI and demonstrated complete regression of the tumors that was not achieved by irradiation alone or with the addition of temozolomide.Conclusions Inhibition of SDF-1 following tumor irradiation is a powerful way of improving tumor response of glioblastoma multiforme.
    Full-text · Article · Dec 2013 · Neuro-Oncology
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