Gliadel Wafer Implantation Combined With Standard Radiotherapy and Concurrent Followed by Adjuvant Temozolomide for Treatment of Newly Diagnosed High-Grade Glioma: A Systematic Literature Review

Since 2003, only two chemotherapeutic agents, evaluated in phase III trials, have been approved by the US Food and Drug Administration for treatment of newly diagnosed high-grade glioma (HGG): Gliadel wafers (intracranially implanted local chemotherapy) and temozolomide (TMZ) (systemic chemotherapy). Neither agent is curative, but each has been shown to improve median overall survival (OS) compared to radiotherapy (RT) alone. To date, no phase III trial has tested these agents when used in sequential combination; however, a number of smaller trials have reported favorable results. We performed a systematic literature review to evaluate the combination of Gliadel wafers with standard RT (60 Gy) plus concurrent and adjuvant TMZ (RT/TMZ) for newly diagnosed HGG. A literature search was conducted for the period of January 1995 to September 2015. Data were extracted and categorized, and means and ranges were determined. A total of 11 publications met criteria, three prospective trials and eight retrospective studies, representing 411 patients who received Gliadel plus standard RT/TMZ. Patients were similar in age, gender, and performance status. The weighted mean of median OS was 18.2 months (ten trials, n = 379, range 12.7 to 21.3 months), and the weighted mean of median progression-free survival was 9.7 months (seven trials, n = 287, range 7 to 12.9 months). The most commonly reported grade 3 and 4 adverse events were myelosuppression (10.22 %), neurologic deficit (7.8 %), and healing abnormalities (4.3 %). Adverse events reflected the distinct independent safety profiles of Gliadel wafers and RT/TMZ, with little evidence of enhanced toxicity from their use in sequential combination. In the 11 identified trials, an increased benefit from sequentially combining Gliadel wafers with RT/TMZ was strongly suggested. Median OS tended to be improved by 3 to 4 months beyond that observed for Gliadel wafers or TMZ when used alone in the respective phase III trials. Larger prospective trials of Gliadel plus RT/TMZ are warranted

Gliadel Wafer Implantation Combined With Standard Radiotherapy and Concurrent Followed by Adjuvant Temozolomide for Treatment of Newly Diagnosed High-Grade Glioma: A Systematic Literature Review

Since 2003, only two chemotherapeutic agents, evaluated in phase III trials, have been approved by the US Food and Drug Administration for treatment of newly diagnosed high-grade glioma (HGG): Gliadel wafers (intracranially implanted local chemotherapy) and temozolomide (TMZ) (systemic chemotherapy). Neither agent is curative, but each has been shown to improve median overall survival (OS) compared to radiotherapy (RT) alone. To date, no phase III trial has tested these agents when used in sequential combination; however, a number of smaller trials have reported favorable results. We performed a systematic literature review to evaluate the combination of Gliadel wafers with standard RT (60 Gy) plus concurrent and adjuvant TMZ (RT/TMZ) for newly diagnosed HGG. A literature search was conducted for the period of January 1995 to September 2015. Data were extracted and categorized, and means and ranges were determined. A total of 11 publications met criteria, three prospective trials and eight retrospective studies, representing 411 patients who received Gliadel plus standard RT/TMZ. Patients were similar in age, gender, and performance status. The weighted mean of median OS was 18.2 months (ten trials, n = 379, range 12.7 to 21.3 months), and the weighted mean of median progression-free survival was 9.7 months (seven trials, n = 287, range 7 to 12.9 months). The most commonly reported grade 3 and 4 adverse events were myelosuppression (10.22 %), neurologic deficit (7.8 %), and healing abnormalities (4.3 %). Adverse events reflected the distinct independent safety profiles of Gliadel wafers and RT/TMZ, with little evidence of enhanced toxicity from their use in sequential combination. In the 11 identified trials, an increased benefit from sequentially combining Gliadel wafers with RT/TMZ was strongly suggested. Median OS tended to be improved by 3 to 4 months beyond that observed for Gliadel wafers or TMZ when used alone in the respective phase III trials. Larger prospective trials of Gliadel plus RT/TMZ are warranted

The c-Met receptor tyrosine kinase inhibitor MP470 radiosensitizes glioblastoma cells

<p>Abstract</p> <p>Purpose</p> <p>Glioblastoma multiforme (GBM) is resistant to current cytotoxic therapies, in part because of enhanced DNA repair. Activation of the receptor tyrosine kinase c-Met has been shown to protect cancer cells from DNA damage. We hypothesized that inhibiting c-Met would decrease this protection and thus sensitize resistant tumor cells to the effects of radiation therapy.</p> <p>Materials and methods</p> <p>Eight human GBM cell lines were screened for radiosensitivity to the small-molecule c-Met inhibitor MP470 with colony-count assays. Double-strand (ds) DNA breaks was quantified by using antibodies to gamma H2AX. Western blotting demonstrate expression of RAD51, glycogen synthase kinase (GSK)-3β, and other proteins. A murine xenograft tumor flank model was used for <it>in vivo </it>radiosensitization studies.</p> <p>Results</p> <p>MP470 reduced c-Met phosphorylation and enhanced radiation-induced cell kill by 0.4 logs in SF767 cells. Cells pretreated with MP470 had more ds DNA damage than cells treated with radiation alone. Mechanistically, MP470 was shown to inhibit dsDNA break repair and increase apoptosis. MP470 influences various survival and DNA repair related proteins such as pAKT, RAD51 and GSK3β. <it>In vivo</it>, the addition of MP470 to radiation resulted in a tumor-growth-delay enhancement ratio of 2.9 over radiation alone and extended survival time.</p> <p>Conclusions</p> <p>GBM is a disease site where radiation is often used to address both macroscopic and microscopic disease. Despite attempts at dose escalation outcomes remain poor. MP470, a potent small-molecule tyrosine kinase inhibitor of c-Met, radiosensitized several GBM cell lines both <it>in vitro </it>and <it>in vivo</it>, and may help to improve outcomes for patients with GBM.</p

The feasibility of using ultrasound during follow-up for superficial non-melanoma skin cancers after electronic brachytherapy

Purpose : Non-melanoma skin cancers (NMSCs) can be treated with a number of modalities including surgery, topical chemotherapy, or radiotherapy. Amongst the radiotherapeutic options, electronic brachytherapy (eBT) is an appealing treatment as it is usually given in a few fractions, it leads to good outcomes, and is increasingly being used. However, currently no follow-up imaging is routinely used or recommended to evaluate treatment response of NMSC. We aimed to use ultrasound (US) in follow-up after eBT for superficial NMSC to assess its feasibility in detecting possible tumor response. Material and methods : Fourteen patients were treated between 2013-2015 for a NMSC using eBT. US guidance was used for treatment planning prior to eBT initiation. After completion of eBT, patients were seen in follow-up for both clinical exam and a repeat US at 1 month to evaluate if tumor response was detectable. Results : Of the 14 patients, 6 were male and 8 were female. The mean age was 71 years. With a median follow-up of 20.5 months, all patients had a complete response based on physical exam. Eleven patients appeared to have a complete response based on US obtained > 1 month after completing eBT. To date, there have been no local recurrences or progression, and all patients are alive. Conclusions : US is an objective imaging modality that may be able to assess NMSC response after eBT. Based on follow-up imaging, further treatment or observation may be recommended. Although this study is hypothesis generating, larger studies with pathologic confirmation of recurrences would be needed to validate US use for follow-up, avoiding possible painful and scarring biopsies in case of low suspicion of recurrence

Long-term benefit of electron beam radiation therapy in the treatment of scleredema of Buschke

Introduction: Scleredema of Buschke is a rare connective tissue disorder presenting with woody thickening and induration of the nuchal and shoulder regions resulting in progressive decrease in the range of motion of the neck. Treatment options include several forms of systemic therapy with variable results. Local radiation therapy (RT) is often thought of as a secondary form of therapy. Few reports exist in the literature about the durability of its benefit, however. Here, we present a case report with the longest known follow-up after primary treatment with electron beam RT. Methods: The patient was treated using 8-MeV en face electrons with 2000 cGy in 10 fractions with 2 separate but matched electron fields. The treatment fields included the posterior neck from the occiput superiorly to the mid-thoracic spine inferiorly with the lateral borders extending to the scapulae. The patient received no additional therapy either pre- or post-RT. Clinical follow-up was obtained at regular intervals. Published literature regarding RT for this disease was reviewed and consolidated. Results: The patient was followed at regular intervals for 6 years with significant softening of the plaque starting at 2 months after RT, resulting in decrease in plaque size by 50% after 18 months. The patient regained 45° of lateral, bidirectional cervical motion from central axis and 50% improvement in neck extension that has remained durable 6 years after treatment with no additional therapy. Quality of life was restored with a simple nontoxic treatment limited to transient, grade 1 fatigue. Conclusion: Scleredema of Buschke is a rare connective tissue disorder commonly treated with multimodal therapy, but it can be effectively and durably controlled with RT alone. This case report documents the durability of the benefit achieved with RT and suggests that RT should be considered earlier in the treatment of this disease