Fractionated radiotherapy is the main stimulus for the induction of cell death and of Hsp70 release of p53 mutated glioblastoma cell lines

Yvonne Rubner , Carolin Muth ,  Annedore Strnad , Anja Derer ,Renate Sieber , Rolf Buslei ,  Benjamin Frey , Rainer Fietkau ,  Udo S Gaipl  

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David Muñoz Carmona
Hospital Juan Ramón Jiménez

Background

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Despite a multimodal therapy consisting of resection followed by fractionated radiotherapy (RT) combined with the chemotherapeutic agent (CT) temozolomide (TMZ), its recurrence is almost inevitable. Since the immune system is capable of eliminating small tumor masses, a therapy should also aim to stimulate anti-tumor immune responses by induction of immunogenic cell death forms. The histone deacetylase inhibitor valproic acid (VPA) might foster this.

Methods

Reflecting therapy standards, we applied in our in vitro model fractionated RT with a single dose of 2Gy and clinically relevant concentrations of CT. Not only the impact of RT and/or CT with TMZ and/or VPA on the clonogenic potential and cell cycle of the glioblastoma cell lines T98G, U251MG, and U87MG was analyzed, but also the resulting cell death forms and release of danger signals such as heat-shock protein70 (Hsp70) and high-mobility group protein B1 (HMGB1).

Results

The clonogenic assays revealed that T98G and U251MG, having mutated tumor suppressor protein p53, are more resistant to RT and CT than U87MG with wild type (WT) p53. In all glioblastoma cells lines, fractionated RT induced a G2 cell cycle arrest, but only in the case of U87MG, TMZ and/or VPA alone resulted in this cell cycle block. Further, fractionated RT significantly increased the number of apoptotic and necrotic tumor cells in all three cell lines. However, only in U87MG, the treatment with TMZ and/or VPA alone, or in combination with fractionated RT, induced significantly more cell death compared to untreated or irradiated controls. While necrotic glioblastoma cells were present after VPA, TMZ especially led to significantly increased amounts of U87MG cells in the radiosensitive G2 cell cycle phase. While CT did not impact on the release of Hsp70, fractionated RT resulted in significantly increased extracellular concentrations of Hsp70 in p53 mutated and WT glioblastoma cells.

Conclusions

Our results indicate that fractionated RT is the main stimulus for induction of glioblastoma cell death forms with immunogenic potential. The generated tumor cell microenvironment might be beneficial to include immune therapies for GBM in the future.

Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials

Early Breast Cancer Trialists' Collaborative Group

Tomado de The Lancet, Early Online Publication, 

Summary

Background

Postmastectomy radiotherapy was shown in previous meta-analyses to reduce the risks of both recurrence and breast cancer mortality in all women with node-positive disease considered together. However, the benefit in women with only one to three positive lymph nodes is uncertain. We aimed to assess the effect of radiotherapy in these women after mastectomy and axillary dissection.

Methods

We did a meta-analysis of individual data for 8135 women randomly assigned to treatment groups during 1964—86 in 22 trials of radiotherapy to the chest wall and regional lymph nodes after mastectomy and axillary surgery versus the same surgery but no radiotherapy. Follow-up lasted 10 years for recurrence and to Jan 1, 2009, for mortality. Analyses were stratified by trial, individual follow-up year, age at entry, and pathological nodal status.

Findings

3786 women had axillary dissection to at least level II and had zero, one to three, or four or more positive nodes. All were in trials in which radiotherapy included the chest wall, supraclavicular or axillary fossa (or both), and internal mammary chain. For 700 women with axillary dissection and no positive nodes, radiotherapy had no significant effect on locoregional recurrence (two-sided significance level [2p]>0·1), overall recurrence (rate ratio [RR], irradiated vs not, 1·06, 95% CI 0·76—1·48, 2p>0·1), or breast cancer mortality (RR 1·18, 95% CI 0·89—1·55, 2p>0·1). For 1314 women with axillary dissection and one to three positive nodes, radiotherapy reduced locoregional recurrence (2p<0 0="" 1133="" 1314="" 1772="" 2p="0·04).</div" 95="" again="" and="" axillary="" both="" breast="" cancer="" ci="" cyclophosphamide="" dissection="" fluorouracil="" for="" four="" given="" groups="" in="" locoregional="" methotrexate="" more="" mortality="" nodes="" of="" or="" overall="" p="" positive="" radiotherapy="" recurrence="" reduced="" systemic="" tamoxifen="" them="" therapy="" these="" trial="" trials="" was="" were="" which="" with="" women="">

Interpretation

After mastectomy and axillary dissection, radiotherapy reduced both recurrence and breast cancer mortality in the women with one to three positive lymph nodes in these trials even when systemic therapy was given. For today's women, who in many countries are at lower risk of recurrence, absolute gains might be smaller but proportional gains might be larger because of more effective radiotherapy.

Funding

Cancer Research UK, British Heart Foundation, UK Medical Research Council.

Conventional Chemo Bests Tyrosine Kinase Inhibitors in Wild-Type Lung Cancers

Frontline Medical News, 2014 Apr 08, MA Moon

News

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David Muñoz Carmona

Conventional chemotherapy prolonged progression-free survival and induced a higher tumor response rate, compared with tyrosine kinase inhibitors, in a meta-analysis involving 1,605 patients with advanced wild-type non–small cell lung cancer, according to a report published online April 8 in JAMA.

First-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors such as erlotinib and gefitinib are first-line treatments for non–small cell lung cancers that are known to harbor EGFR-activating mutations, but their benefit is less pronounced against wild-type NSCLCs (no mutation detected in the EGFR gene). Several small studies assessing the efficacy of these agents in wild-type NSCLCs have produced inconclusive results, mostly because of the small number of participating patients, said Dr. June-Koo Lee of the department of internal medicine, Seoul (Republic of Korea) National University Hospital, and associates.

The investigators therefore pooled data from a meta-analysis of 11 randomized, controlled, open-label trials, to obtain sufficient data to compare EGFR tyrosine kinase inhibitors (811 patients) against conventional chemotherapeutic agents such as cisplatin, carboplatin, docetaxel, and pemetrexed (794 patients) in wild-type NSCLCs.

Progression-free survival was significantly longer with conventional chemotherapy than with EGFR tyrosine kinase inhibitors (6.4 vs 1.9 months; hazard ratio, 1.41; 95% confidence interval, 1.10-1.81). Conventional chemotherapy also induced a significantly higher objective response rate than did tyrosine kinase inhibitors (16.8% vs 7.2%; relative risk of nonresponse from tyrosine kinase inhibitors, 1.11; 95% CI, 1.02-1.21).

Overall survival was not significantly different between the two study groups, but that “can be explained by the large crossover rates of the included trials,” Dr. Lee and associates reported (JAMA 2014;311:1430-7).

The findings “suggest that current guidelines recommending EGFR tyrosine kinase inhibitors as a standard treatment in this setting ... may need to be reevaluated,” they wrote.

However, it is important to note that a treatment’s toxicity profile is crucial when choosing among different options, and EGFR tyrosine kinase inhibitors are known to have a better toxicity profile than standard chemotherapeutic agents. They should therefore be considered for certain patients, such as those who have a poor performance status, the investigators said.

This study was supported in part by the National Research Foundation of Korea. Dr. Lee reported no financial conflicts of interest; two coauthors reported ties to Pfizer, Lilly, and other companies.

Radiotherapy for Early Breast Cancer and 1 to 3 Positive Nodes

Zosia Chustecka

March 19, 2014

Medscape Medical News > Conference News

GLASGOW, Scotland — For women with early breast cancer who undergo mastectomy and axillary dissection, radiotherapy is recommended for those who are found to have 4 or more positive lymph nodes, but is not usually given to women who are found to be node-negative.

However, for the women who fall into the gray area in between, who are found to have 1 to 3 positive axillary nodes, there has been insufficient evidence to make a recommendation one way or another.

Now there are data to show that radiation is also beneficial in this group.

The results were presented March 19 here at the 9th European Breast Cancer Conference, and published onlinesimultaneously in the Lancet.

The finding comes from a meta-analysis of individual data for a total of 8135 women participating in clinical trials who were followed for an average of 11 years; 1314 of these women were found to have 1 to 3 positive nodes.

The results for this subgroup of women showed that postmastectomy radiotherapy significantly reduced both recurrence and breast cancer mortality, even when systemic therapy was given.

The meta-analysis was conducted by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), and presented at the meeting by Paul McGale, PhD, senior statistician at the University of Oxford, United Kingdom.

In women who had 1 to 3 positive nodes, postmastectomy radiotherapy reduced the recurrence rate by 32% and reduced the breast cancer mortality rate by 20%. The benefit was similar whether women had only 1 positive node or whether they had 2 or 3 positive nodes.

"Giving radiotherapy to these women led to nearly 12 fewer recurrences per 100 women after 10 years and 8 fewer deaths per 100 women after 20 years," Dr. McGale said in a statement.

The results from the meta-analysis also confirmed previous findings of benefit from radiotherapy for women with 4 or more positive nodes, and the lack of benefit for women with node-negative disease.

For women with 4 or more positive nodes (n = 1772), the meta-analysis showed that radiotherapy reduced overall recurrence by 21% and breast cancer mortality by 13%. In other words, radiotherapy for these women led to 9 fewer recurrences per 100 women after 10 years, and 9 fewer breast cancer deaths per 100 women after 20 years.

These results are statistically similar to those found for the subgroup of women with 1 to 3 positive nodes, commented coauthor Carolyn Taylor, FRCR, a clinical oncologist at Oxford University Hospitals and a clinical research fellow at the University of Oxford. She noted that the women with more positive nodes would be at a higher risk for recurrence, but the proportional reduction in risk was similar to that seen in women with fewer positive nodes.

In this meta-analysis, a total of 5821 women had node-positive disease; of these, 3131 (54%) had axillary dissection (defined as removal of axillary lymph nodes in at least levels I and II) and 2541 (44%) had axillary sampling (less extensive axillary surgery), while for 149 (2%), the extent of axillary surgery was unknown.

The meta-analysis also confirmed that there was no significant benefit from radiotherapy for women who were found to be node-negative (n = 700). "There was no evidence that radiotherapy provided any benefit" in this group, the researchers write.

Benefit Seen Regardless of Chemotherapy

"Another result from our study is that the proportional benefits of radiotherapy were similar in women regardless of whether or not they had also received chemotherapy or hormonal therapy," Dr. McGale said. The most common chemotherapy used in the trials was cyclophosphamide, methotrexate, and fluorouracil, and the most common hormonal therapy used was tamoxifen

"This is important because most women today receive these therapies. Our results suggest that women being treated today are likely also to benefit from radiotherapy if they have any positive lymph nodes," he added.

The meta-analysis included trials that were conducted between 1964 and 1986.

"Since the time when the women in these trials were randomized, there have been advances in radiotherapy and also in breast screening, surgery, lymph node staging, and systemic therapy," Dr. McGale commented. "So the absolute benefits from postmastectomy radiotherapy today may be smaller than those we have reported here. But the proportional benefits from radiotherapy are likely to be at least as big."