Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group

Abstract Background Advanced radiotherapeutic treatment techniques limit the cognitive morbidity associated with whole-brain radiotherapy (WBRT) for brain metastasis through avoidance of hippocampal structures. However, achieving durable intracranial control remains challenging. Methods We conducted a single-institution single-arm phase II trial of hippocampal-sparing whole brain irradiation with simultaneous integrated boost (HSIB-WBRT) to metastatic deposits in adult patients with brain metastasis. Radiation therapy consisted of intensity-modulated radiation therapy delivering 20 Gy in 10 fractions over 2–2.5 weeks to the whole brain with a simultaneous integrated boost of 40 Gy in 10 fractions to metastatic lesions. Hippocampal regions were limited to 16 Gy. Cognitive performance and cancer outcomes were evaluated. Results A total of 50 patients, median age 60 years (interquartile range, 54–65), were enrolled. Median progression-free survival was 2.9 months (95% CI: 1.5–4.0) and overall survival was 9 months. As expected, poor survival and end-of-life considerations resulted in a high exclusion rate from cognitive testing. Nevertheless, mean decline in Hopkins Verbal Learning Test–Revised delayed recall (HVLT-R DR) at 3 months after HSIB-WBRT was only 10.6% (95% CI: −36.5‒15.3%). Cumulative incidence of local and intracranial failure with death as a competing risk was 8.8% (95% CI: 2.7‒19.6%) and 21.3% (95% CI: 10.7‒34.2%) at 1 year, respectively. Three grade 3 toxicities consisting of nausea, vomiting, and necrosis or headache were observed in 3 patients. Scores on the Multidimensional Fatigue Inventory 20 remained stable for evaluable patients at 3 months. Conclusions HVLT-R DR after HSIB-WBRT was significantly improved compared with historical outcomes in patients treated with traditional WBRT, while achieving intracranial control similar to patients treated with WBRT plus stereotactic radiosurgery (SRS). This technique can be considered in select patients with multiple brain metastases who cannot otherwise receive SRS.

Download Full-text

Final results of a multicentre phase II trial of high-dose methotrexate (HD-MTX), cytarabine, thiotepa, and idarubicin (MATILDE regimen) followed by whole-brain irradiation (WBRT) for primary CNS lymphomas (PCNSL)

Journal of Clinical Oncology ◽

10.1200/jco.2005.23.16_suppl.1530 ◽

2005 ◽

Vol 23 (16_suppl) ◽

pp. 1530-1530

Author(s):

A. J. Ferreri ◽

S. Dell’oro ◽

M. Foppoli ◽

A. A. Brandes ◽

M. Montanari ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Trial ◽

High Dose ◽

High Dose Methotrexate ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Multicentre Phase ◽

Brain Irradiation ◽

Dose Methotrexate ◽

Cns Lymphomas

Download Full-text

Concomitant and adjuvant temozolomide (TMZ) and whole brain irradiation (WBI) on patients affected with brain metastases (BM): a randomized multicentric phase II trial

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/s0360-3016(03)00837-x ◽

2003 ◽

Vol 57 (2) ◽

pp. S132 ◽

Cited By ~ 2

Author(s):

S Villa ◽

E Verger ◽

M Gil ◽

N Vinolas ◽

R Yaya ◽

...

Keyword(s):

Brain Metastases ◽

Phase Ii ◽

Phase Ii Trial ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

Adjuvant Temozolomide

Download Full-text

Metabolic and histopathological changes in the brain and plasma of rats exposed to fractionated whole-brain irradiation

Brain Research ◽

10.1016/j.brainres.2018.12.022 ◽

2019 ◽

Vol 1708 ◽

pp. 146-159 ◽

Cited By ~ 1

Author(s):

Soňa Bálentová ◽

Petra Hnilicová ◽

Dagmar Kalenská ◽

Eva Baranovičová ◽

Peter Muríň ◽

...

Keyword(s):

Histopathological Changes ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

The Brain

Download Full-text

Dosimetric study of whole-brain irradiation with high-energy photon beams for dose reduction to the scalp

British Journal of Radiology ◽

10.1259/bjr.20200159 ◽

2020 ◽

Vol 93 (1114) ◽

pp. 20200159

Author(s):

Masafumi Sawada ◽

Etsuo Kunieda ◽

Takeshi Akiba ◽

Shigeto Kabuki ◽

Ryuta Nagao ◽

...

Keyword(s):

High Energy ◽

High Energy Photon ◽

Photon Beams ◽

Whole Brain Irradiation ◽

Energy Photon ◽

Whole Brain ◽

Brain Irradiation ◽

Brain Surface ◽

The Mean ◽

The Brain

Objective: To evaluate the efficiency of high-energy photons for mitigating alopecia due to whole-brain irradiation (WBRT). Methods: Planning CT data from 10 patients who received WBRT were collected. We prepared 4 WBRT plans that used 6 or 15 MV photon beams, with or without use of a field-in-field (FiF) technique, and compared outcomes using a treatment planning system. The primary outcome was dose parameters to the scalp, including the mean dose, maximum dose, and dose received to 50% scalp (D50%). Secondary outcomes were minimum dose to the brain surface. Results: Using FiF, the mean doses were 24.4–26.0 and 22.4–24.1 Gy, and the maximum doses were 30.5–32.1 and 28.5–30.8 Gy for 6 and 15 MV photon beams, respectively. Without FiF, the mean doses were 24.6–26.9 and 22.6–24.5 Gy, and the maximum doses were 30.8–34.6 and 28.6–32.4 Gy for 6 and 15 MV photon beams. The 15 MV plan resulted in a lower scalp dose for each dose parameter (p < 0.001). Using FiF, the minimum doses to the brain surface for the 6 and 15 MV plans were 28.9 ± 0.440 and 29.0 ± 0.557 Gy, respectively (p = 0.70). Without FiF, the minimum doses to the brain surface for the 6 and 15 MV plans were 28.9 ± 0.456 and 29.0 ± 0.529, respectively (p = 0.66). Conclusion: Compared with the 6 MV plan, the 15 MV plan achieved a lower scalp dose without impairing the brain surface dose. Advances in knowledge: High-energy photon WBRT may mitigate alopecia of patients who receiving WBRT.

Download Full-text

Randomized phase II trial on primary chemotherapy with high-dose methotrexate (HD-MTX) alone or associated with high-dose cytarabine (HD-araC) for patients with primary CNS lymphoma (I.E.L.S.G. #20 Trial): Tolerability, activity, and survival analyses

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8545 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8545-8545

Author(s):

A. J. Ferreri ◽

M. Reni ◽

M. Martelli ◽

G. Pangalis ◽

M. Frezzato ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Trial ◽

Primary Cns Lymphoma ◽

Cns Lymphoma ◽

High Dose ◽

Whole Brain Irradiation ◽

Brain Irradiation ◽

Randomized Phase Ii ◽

Ecog Ps

8545 Background: HD-MTX-based chemotherapy (cht) is the conventional approach to primary CNS lymphoma (PCNSL), but superiority of polycht over HD-MTX alone is unproven. A benefit of adding HD-araC to MTX has been suggested. This is a randomized phase II trial comparing HD-MTX monocht versus HD-MTX plus HD-araC as primary cht in immunocompetent patients (pts) with PCNSL. Methods: 79 HIV- pts with newly diagnosed PCNSL, age 18–75 ys, ECOG-PS≤3, and measurable disease were randomly assigned to receive 4 courses (interval 3 weeks) of MTX 3.5 g/mq (control arm; n=40) or MTX (same dose) + araC 2 g/mq × 2/d, d 2–3 (experimental arm; n=39). Cht was followed by whole-brain irradiation. Pts were stratified based on IELSG score and centre irradiation policy for pts >60 ys in complete remission (CR) after cht. CR rate (CRR) after cht was the primary endpoint; planned accrual (α=.05 β=.2) for P0 30% and P1 50% was 39 pts/arm. Results: Median age of the 79 entered pts was 58 ys (range 25–74). No differences in clinical presentation between arms were observed. Two hundred thirty-one (73%) of the 316 planned courses were actually delivered (MTX 71%; MTX+araC 76%). Causes of cht interruption were: progressive disease in 20 MTX and 8 MTX+araC pts, toxicity in 1 MTX and 7 MTX+araC pts and refusal in 2 MTX+araC pts. As expected, neutropenia, thrombocytopenia and infections were more common in MTX+araC arm. All G3–4 non-hematological toxicities were <5%. One MTX pt and 3 MTX+araC pts died of toxicity. CRR was 18% after MTX and 46% after MTX+araC (p=0.006), with an ORR of 40% and 69% (p=0.009), respectively. At a median follow-up of 30 m., 31 MTX and 22 MTX+araC pts experienced failure, with a 3-yr FFS of 21±6% and 38±8% (p=0.01), respectively. No differences in relapse sites or salvage efficacy between treatment arms were observed. Twelve MTX and 20 MTX+araC pts are alive, with a 3-yr OS of 32±8% and 46±9% (p=0.07). Conclusions: This is the first randomized trial on PCNSL with completed accrual. The addition of HD-araC to HD-MTX resulted in significantly better outcome and acceptable toxicity. MTX+araC may be the cht combination used as control arm in future randomized trials. No significant financial relationships to disclose.

Download Full-text

Chemotherapy for patients with brain metastases from melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e19012 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e19012-e19012

Author(s):

David R. Naskhletashvili ◽

Vera A. Gorbunova ◽

Mark B. Bychkov ◽

Ali H. Bekyashev ◽

Vladislav B. Karahan ◽

...

Keyword(s):

Partial Response ◽

Brain Metastases ◽

Metastatic Melanoma ◽

Objective Response ◽

Complete Response ◽

Combined Chemotherapy ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

The Brain

e19012 Background: There have not been standards of chemo- and chemo-radiotherapy for treatment for patients with brain metastases. The patients (pts) with brain metastases (BM) from melanoma have poor prognoses. The main goal of this trial is to assess the efficacy of nitrosoureas (CCNU or FCNU), temozolomide (TMZ) as monotherapy, TMZ combined with whole brain irradiation (WBI), or combined chemotherapy of TMZ and cisplatin in pts with BM from melanoma. Methods: 78 pts were included in this study. 21 pts were treated with WBI (3Gy/30Gy) and concomitant TMZ therapy (75 mg/m2/day orally on days 1-14), 19 pts were treated with TMZ (150 mg/m2/day orally on days 1-5, every 4 weeks) as monotherapy, 17 pts pts were treated with nitrosoureas (CCNU or FCNU), 21 pts were treated with combined chemotherapy of TMZ (150/mg/m2/day orally on days 1-5, every 4 weeks) + cisplatin (20/mg/m2/day intravenous on days 1-5, every 4 weeks). The main aims of this study were objective response (OR) – complete response (CR) + partial response (PR) in the brain and in the extracranial sites (ES), median of survival (mOS), 1-year and 2-year survival. Results: Observations were as follows: in the TMZ + WBI treated pts, 4 OR (19,0%) in 21 pts group in the brain and 1 OR (6,7%) in 15 pts group in ES. The mOS was 6.0 months, 1-year survival was 23,8%. In the TMZ monotherapy treated pts there were 5 OR (26,3%) in 19 pts group in the brain and no OR in 13 pts group in ES. The mOS was 6 months, 1-year survival was 21,1%. In the nitrisoureas treated pts we achieved 2 OR (11,8%) in 17 pts group in the brain and 1 OR (9,1%) in 11 pts group in ES. The mOS was 5 months, 1-year survival was 17,6%. In the TMZ + cisplatin treated pts there were 7 OR (33.3%) in 21 pts group in the brain and 7 OR (35,0%) in 20 pts group in ES. The mOS was 8 months, 1-year survival was 33,3%. 2-year survival (19,0%) was achieved only in TMZ and cisplatin group. Conclusions: Previous results of our study showed promising higher efficacy of TMZ and cisplatin, especially in OR in ES (p<0.05) and in 2-year survival (p<0.05), in comparison with TMZ alone, nitrosoureas or TMZ with whole brain irradiation in patients with metastatic melanoma with BM. Control of extracranial lesions is important factor for patients with BM. Further investigation is to be expected.

Download Full-text