IL-1β induces IL-6 production and increases invasiveness and estrogen-independent growth in a TG2-dependent manner in human breast cancer cells

Abstract

Background

We previously reported that IL-6 and transglutaminase 2 (TG2) were expressed in more aggressive basal-like breast cancer cells, and TG2 and IL-6 expression gave these cells stem-cell-like phenotypes, increased invasive ability, and increased metastatic potential. In the present study, the underlying mechanism by which IL-6 production is induced in luminal-type breast cancer cells was evaluated, and TG2 overexpression, IL-1β stimulation, and IL-6 expression were found to give cancerous cells a hormone-independent phenotype.

Methods

Luminal-type breast cancer cells (MCF7 cells) were stably transfected with TG2. To evaluate the requirement for IL-6 neogenesis, MCF7 cells were stimulated with various cytokines. To evaluate tumorigenesis, cancer cells were grown in a three-dimensional culture system and grafted into the mammary fat pads of NOD/scid/IL-2Rγ^−/− mice.

Results

IL-1β induced IL-6 production in TG2-expressing MCF7 cells through an NF-kB-, PI3K-, and JNK-dependent mechanism. IL-1β increased stem-cell-like phenotypes, invasiveness, survival in a three-dimensional culture model, and estrogen-independent tumor growth of TG2-expressing MCF7 cells, which was attenuated by either anti-IL-6 or anti-IL-1β antibody treatment.

Conclusion

Within the inflammatory tumor microenvironment, IL-1β increases luminal-type breast cancer cell aggressiveness by stimulating IL-6 production through a TG2-dependent mechanism.

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In vivo bioluminescence imaging for leptomeningeal dissemination of medulloblastoma in mouse models

Abstract

Background

The primary cause of treatment failure in medulloblastomas (MB) is the development of leptomeningeal dissemination (seeding). For translational research on MB seeding, one of the major challenges is the development of reliable experimental models that simulate the seeding and growth characteristics of MBs. To overcome this obstacle, we improved an experimental mouse model by intracisternal inoculation of human MB cells and monitoring with in vivo live images.

Methods

Human MB cells (UW426, D283 and MED8A) were transfected with a firefly luciferase gene and a Thy1.1 (CD90.1) marker linked with IRES under the control of the CMV promoter in a retroviral DNA backbone (effLuc). The MB-effLuc cells were injected into the cisterna magna using an intrathecal catheter, and bioluminescence images were captured. We performed histopathological analysis to confirm the extent of tumor seeding.

Results

The luciferase activity of MB-effLuc cells displayed a gradually increasing pattern, which correlated with a quantitative luminometric assay. Live imaging showed that the MB-effLuc cells were diffusely distributed in the cervical spinal cord and the lumbosacral area. All mice injected with UW426-effLuc, D283-effLuc and MED8A-effLuc died within 51 days. The median survival was 22, 41 and 12 days after injection of 1.2 × 10⁶ UW426-effLuc, D283-effLuc and MED8A-effLuc cells, respectively. The histopathological studies revealed that the MB-effLuc cells spread extensively and diffusely along the leptomeninges of the brain and spinal cord, forming tumor cell-coated layers. The tumor cells in the subarachnoid space expressed a human nuclei marker and Ki-67. Compared with the intracerebellar injection method in which the subfrontal area and distal spinal cord were spared by tumor cell seeding in some mice, the intracisternal injection model more closely resembled the widespread leptomeningeal seeding observed in MB patients.

Conclusion

The results and described method are valuable resources for further translational research to overcome MB seeding.

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Oxidative stress in prostate hyperplasia and carcinogenesis

Prostatic hyperplasia (PH) is a common urologic disease that affects mostly elderly men. PH can be classified as benign prostatic hyperplasia (BPH), or prostate cancer (PCa) based on its severity. Oxidative st...

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Non-internalizing SMDCs for Renal Cell Carcinomas

In most cases, cytotoxic drugs do not preferentially accumulate at the tumor site, causing unwant-ed toxicities and preventing dose escalation to therapeutically active regimens. Here, we show that acetazolamide derivatives, which bind to carbonic anhydrase IX (CAIX) on the surface of kidney cancer cells, selectively deliver payloads at the site of disease, sparing normal organs. Bi-odistribution studies, performed in tumor-bearing mice with acetazolamide derivatives bearing a technetium-99m chelator complex or a red fluorophore as payload, revealed a preferential tumor accumulation of the compound at doses up to 560 nmol/Kg. The percentage of injected dose per gram in the tumor was dose-dependent and revealed optimal tumor:organ ratios at 140 nmol/Kg, with a tumor:blood ratio of 80:1 at 6 h. Acetazolamide, coupled to potent cytotoxic drugs via a dipeptide linker, exhibited a potent antitumor activity in nude mice bearing SKRC-52 renal cell carcinomas, while drug derivatives devoid of the acetazolamide moiety did not exhibit any de-tectable anticancer activity at the same doses. The observation of tumor regression with a non-internalizing ligand and with different cytotoxic moieties (MMAE and PNU-159682) indicates a general mechanism of action, based on the selective accumulation of the product on tumor cells, followed by the extracellular proteolytic release of the cytotoxic payload at the neoplastic site and the subsequent drug internalization into tumor cells. Acetazolamide-based drug conjugates may represent a promising class of targeted agents for the treatment of metastatic kidney cancer, as the majority of human clear cell renal cell carcinomas are strongly positive for CAIX.

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Alectinib in ALK-positive NSCLC

Over the last 2 years, our therapeutic armamentarium against genomically-defined subgroups of non-small cell lung cancer (NSCLC) has extended to patients with acquired resistance to front-line targeted therapy. Alectinib (Alecensa®, CH5424802), a second-generation, orally active, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK), is indicated for patients with metastatic, ALK rearrangement-positive NSCLC whose disease has worsened after treatment with crizotinib or who became intolerant of the drug and it received orphan drug designation, breakthrough therapy designation, priority review status, and accelerated approval by the FDA.

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Imaging tumor metabolism

Changes in tumor metabolism may accompany disease progression and can occur following treatment, often before there are changes in tumor size. We focus here on imaging methods that can be used to image various aspects of tumor metabolism, with an emphasis on methods that can be used for tumor grading, assessing disease progression and monitoring treatment response.

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Effects of In Utero Exposure to Ethinyl Estradiol on Tamoxifen Resistance and Breast Cancer Recurrence in a Preclinical Model

Background: Responses to endocrine therapies vary among patients with estrogen receptor (ER+) breast cancer. We studied whether in utero exposure to endocrine-disrupting compounds might explain these variations.

Methods: We describe a novel ER+ breast cancer model to study de novo and acquired tamoxifen (TAM) resistance. Pregnant Sprague Dawley rats were exposed to 0 or 0.1 ppm ethinyl estradiol (EE2), and the response of 9,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors to 15 mg/kg TAM, with (n = 17 tumors in the controls and n = 20 tumors in EE2 offspring) or without 1.2 g/kg valproic acid and 5 mg/kg hydralazine (n = 24 tumors in the controls and n = 32 tumors in EE2 offspring) in the female offspring, was assessed. One-sided Chi2 tests were used to calculate P values. Comparisons of differentially expressed genes between mammary tumors in in utero EE2-exposed and control rats, and between anti-estrogen-resistant LCC9 and -sensitive LCC1 human breast cancer cells, were also performed.

Results: In our preclinical model, 54.2% of mammary tumors in the control rats exhibited a complete response to TAM, of which 23.1% acquired resistance with continued anti-estrogen treatment and recurred. Mammary tumors in the EE2 offspring were statistically significantly less likely to respond to TAM (P = .047) and recur (P = .007). In the EE2 offspring, but not in controls, adding valproic acid and hydralazine to TAM prevented recurrence (P < .001). Three downregulated and hypermethylated genes (KLF4, LGALS3, MICB) and one upregulated gene (ETV4) were identified in EE2 tumors and LCC9 breast cancer cells, and valproic acid and hydralazine normalized the altered expression of all four genes.

Conclusions: Resistance to TAM may be preprogrammed by in utero exposure to high estrogen levels and mediated through reversible epigenetic alterations in genes associated with epithelial-mesenchymal transition and tumor immune responses.

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Advances in brain metastases presented at the American Society of Clinical Oncology 2016 Annual Meeting: Part II

Future Oncology Ahead of Print.


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Blocking Modification of Eukaryotic Initiation 5A2 Antagonizes Cervical Carcinoma via Inhibition of RhoA/ROCK Signal Transduction Pathway

Cervical carcinoma is one of the leading causes of cancer-related death for female worldwide. Eukaryotic initiation factor 5A2 belongs to the eukaryotic initiation factor 5A family and is proposed to be a key factor involved in the development of diverse cancers. In the current study, a series of in vivo and in vitro investigations were performed to characterize the role of eukaryotic initiation factor 5A2 in oncogenesis and metastasis of cervical carcinoma. The expression status of eukaryotic initiation factor 5A2 in 15 cervical carcinoma patients was quantified. Then, the effect of eukaryotic initiation factor 5A2 knockdown on in vivo tumorigenicity ability, cell proliferation, cell cycle distribution, and cell mobility of HeLa cells was measured. To uncover the mechanism driving the function of eukaryotic initiation factor 5A2 in cervical carcinoma, expression of members within RhoA/ROCK pathway was detected, and the results were further verified with an RhoA overexpression modification. The level of eukaryotic initiation factor 5A2 in cervical carcinoma samples was significantly higher than that in paired paratumor tissues (P < .05). And the in vivo tumorigenic ability of HeLa cells was reduced by inhibition of eukaryotic initiation factor 5A2. Knockdown of eukaryotic initiation factor 5A2 in HeLa cells decreased the cell viability compared with normal cells and induced G1 phase cell cycle arrest (P < .05). Moreover, the cell migration ability of eukaryotic initiation factor 5A2 knockdown cells was dramatically inhibited. Associated with alterations in phenotypes, RhoA, ROCK I, and ROCK II were downregulated. The above-mentioned changes in eukaryotic initiation factor 5A2 knockdown cells were alleviated by the overexpression of RhoA. The major findings outlined in the current study confirmed the potential of eukaryotic initiation factor 5A2 as a promising prognosis predictor and therapeutic target for cervical carcinoma treatment. Also, our data inferred that eukaryotic initiation factor 5A2 might function in carcinogenesis of cervical carcinoma through an RhoA/ROCK-dependent manner.

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Trichomonas vaginalis : a possible foe to prostate cancer

Abstract

Prostate cancer (PCA) is the most common malignancy in men in USA, and the role of Trichomonas vaginalis (T. vag) in the development of PCA is still controversial. Clonogenic assay, PCNA staining, TUNEL staining and caspase-3 activity assay were used to investigate the in vitro role of T. vag in human prostate cancer. We further investigated the possible molecular mechanisms using RT-PCR and immunohistochemical staining. Culture supernatant of T. vag inhibits growth of PC-3 prostate cancer cells, and this correlated with upregulation of p21. Culture supernatant of T. vag induced apoptosis of PC-3 cells, and this correlated with downregulation of Bcl-2. The growth inhibition effect of culture supernatant of T. vag is also demonstrated in another prostate cancer cell line DU145, suggesting that its effect is not specific to one prostate cancer cell line. Culture supernatant of T. vag inhibits growth of prostate cancer by inhibition of proliferation and promotion of apoptosis. Such a study might be helpful to address the association between PCA and infection of T. vag.

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Phase II open-label study of recombinant circularly permuted TRAIL as a single-agent treatment for relapsed or refractory multiple myeloma

Despite the recent development of new therapies, multiple myeloma (MM) remains an incurable disease. Thus, new, effective treatments are urgently needed, particularly for relapsed or refractory MM (RRMM). In a...

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Hippocampal sparing radiotherapy for glioblastoma patients: a planning study using volumetric modulated arc therapy

Abstract

Background

The purpose of this study is to investigate the potential to reduce exposure of the contralateral hippocampus in radiotherapy for glioblastoma using volumetric modulated arc therapy (VMAT).

Methods

Datasets of 27 patients who had received 3D conformal radiotherapy (3D-CRT) for glioblastoma with a prescribed dose of 60Gy in fractions of 2Gy were included in this planning study. VMAT plans were optimized with the aim to reduce the dose to the contralateral hippocampus as much as possible without compromising other parameters. Hippocampal dose and treatment parameters were compared to the 3D-CRT plans using the Wilcoxon signed-rank test. The influence of tumour location and PTV size on the hippocampal dose was investigated with the Mann–Whitney-U-test and Spearman's rank correlation coefficient.

Results

The median reduction of the contralateral hippocampus generalized equivalent uniform dose (gEUD) with VMAT was 36 % compared to the original 3D-CRT plans (p < 0.05). Other dose parameters were maintained or improved. The median V30Gy brain could be reduced by 17.9 % (p < 0.05). For VMAT, a parietal and a non-temporal tumour localisation as well as a larger PTV size were predictors for a higher hippocampal dose (p < 0.05).

Conclusions

Using VMAT, a substantial reduction of the radiotherapy dose to the contralateral hippocampus for patients with glioblastoma is feasible without compromising other treatment parameters. For larger PTV sizes, less sparing can be achieved. Whether this approach is able to preserve the neurocognitive status without compromising the oncological outcome needs to be investigated in the setting of prospective clinical trials.

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Glycogen synthase kinase 3 (GSK3)-inhibitor SB216763 promotes the conversion of human umbilical cord mesenchymal stem cells into neural precursors in adherent culture

Abstract

The ability to generate neural progenitor cells from human umbilical cord mesenchymal stem cells (hUC-MSCs) has provided an option to treat neurodegenerative diseases. To establish a method for this purpose, we characterized the early neural markers of hUC-MSCs-derived cells under different conditions. We found that neither the elimination of signals for alternative fate nor N2 supplement was sufficient to differentiate hUC-MSCs into neural precursor cells, but the GSK3 inhibitor SB216763 could promote an efficient neural commitment of hUC-MSCs. The results indicated that Wnt/β-catenin might play an important role during the early neural differentiation of hUC-MSCs. Here, we report a method for hUC-MSCs to commit efficiently into a neural fate within a short period of time. This protocol provides an efficient method for hUC-MSCs-based neural regeneration.

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Chromosome 17p Homodisomy Is Associated With Better Outcome in 1p19q Non-Codeleted and IDH-Mutated Gliomas

Background.

The 1p19q non-codeleted gliomas with IDH mutation, defined as "molecular astrocytomas," display frequent TP53 mutations and have an intermediate prognosis. We investigated the prognostic impact of copy number-neutral loss of heterozygosity (CNLOH) in 17p in this population.

Methods.

We analyzed 793 gliomas (206 grade II, 377 grade III, and 210 grade IV) by single nucleotide polymorphism array and for TP53 mutations.

Results.

Homodisomy revealed by CNLOH was observed in 156 cases (19.7%). It was more frequent in astrocytomas and oligoastrocytomas (98/256, 38%) than oligodendrogliomas (28/327, 8.6%; p < .0001) or glioblastoma multiforme (30/210, 14.3%; p < .0001), tightly associated with TP53 mutation (69/71 vs. 20/79; p = 2 x 10^–16), and mutually exclusive with 1p19q codeletion (1/156 vs. 249/556; p < .0001). In the group of IDH-mutated 1p19q non-codeleted gliomas, CNLOH 17p was associated with longer survival (86.3 vs. 46.2 months; p = .004), particularly in grade III gliomas (overall survival >100 vs. 37.9 months; p = .007). These data were confirmed in an independent dataset from the Cancer Genome Atlas.

Conclusion.

CNLOH 17p is a prognostic marker and further refines the molecular classification of gliomas.

Implications for Practice:

Homodisomy of chromosome 17p (CNLOH 17p) is a frequent feature in IDH-mutated 1p19q non-codeleted gliomas (group 2). It is constantly associated with TP53 mutation. It was found, within this specific molecular group of gliomas (corresponding to molecular astrocytomas), that CNLOH 17p is associated with a much better outcome and may therefore represent an additional prognostic marker to refine the prognostic classification of gliomas.

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Cost-Effectiveness Analysis of Using Loss of Heterozygosity to Manage Premalignant Oral Dysplasia in British Columbia, Canada

Background.

Management of low-grade oral dysplasias (LGDs) is complicated, as only a small percentage of lesions will progress to invasive disease. The current standard of care requires patients to undergo regular monitoring of their lesions, with intervention occurring as a response to meaningful clinical changes. Recent improvements in molecular technologies and understanding of the biology of LGDs may allow clinicians to manage lesions based on their genome-guided risk.

Methods.

We used a decision-analytic Markov model to estimate the cost-effectiveness of risk-stratified care using a genomic assay. In the experimental arm, patients with LGDs were managed according to their risk profile using the assay, with low- and intermediate-risk patients given longer screening intervals and high-risk patients immediately treated with surgery. Patients in the comparator arm had standard care (biannual follow-up appointments at an oral cancer clinic). Incremental costs and outcomes in life-years gained (LYG) and quality-adjusted life-years (QALY) were calculated based on the results in each arm.

Results.

The mean cost of assay-guided management was $8,123 (95% confidence interval [CI] $2,973 to $23,062 in 2013 Canadian dollars) less than the cost of standard care. This difference was driven largely by reductions in resource use among people who did not develop cancer. Mean incremental effectiveness was 0.18 LYG (95% CI 0.08 to 0.39) or 0.64 QALY (95% CI 0.46 to 0.89). Sensitivity analysis suggests that these findings are robust to both expected and extreme variation in all parameter values.

Conclusion.

Use of the assay-guided management strategy costs less and is more effective than standard management of LGDs.

Implications for Practice:

The findings of this study strongly suggest that the use of a risk-stratification method such as a genomic assay can result in improved quality-adjusted survival outcomes for patients with low-grade oral dysplasia (LGD). The use of such an assay in this study provides "precision medicine," allowing for a change in follow-up frequency or early intervention as compared with current standard care. As genomic technologies become more common in cancer care, it is hoped that such an assay, once validated, will become part of a new model for the standard management of LGDs in similar health systems.

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Thinking Systematically About the Off-Label Use of Cancer Drugs and Combinations for Patients Who Have Exhausted Proven Therapies

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Understanding the Precision in "Precision Medicine"

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BEZ235: When Promising Science Meets Clinical Reality

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Sorafenib Effectiveness in Advanced Hepatocellular Carcinoma

Background.

Phase III trials show sorafenib improves survival in advanced hepatocellular carcinoma (HCC). Because of narrow trial eligibility, results may not be generalizable to a broader HCC population. We sought to evaluate the effectiveness of initial sorafenib versus no treatment among Medicare beneficiaries with advanced HCC.

Materials and Methods.

Patients with advanced HCC diagnosed from 2008 to 2011 were identified from the Surveillance, Epidemiology, and End Results–Medicare database. Eligible patients received initial sorafenib or no therapy and were covered by Medicare parts A, B, and D. Sorafenib use and outcomes were described in this population. Using a propensity score (PS)-matched sample, we compared the effectiveness of sorafenib versus no treatment by Cox proportional hazards and binomial regression, using a landmark requiring all patients to survive ≥60 days after diagnosis.

Results.

Of 1,532 patients, 27% received initial sorafenib. Median duration of sorafenib use was 60 days (interquartile range [IQR], 30–107 days), and median survival from first prescription was 3 months (IQR, 1–8 months). In the PS-matched cohort, median survival was 3 months from the 60-day landmark in sorafenib-treated (n = 223) and 2 months in untreated (n = 223) patients (adjusted hazard ratio, 0.95 [95% confidence interval (CI), 0.78–1.16]). Sorafenib was associated with a nonsignificant reduction in mortality at 3 months (44% versus 51%; adjusted risk ratio, 0.88 [95% CI, 0.72–1.07]), but no reduction thereafter.

Conclusion.

Survival after sorafenib initiation in newly diagnosed Medicare beneficiaries with HCC is exceptionally short, suggesting trial results are not generalizable to all HCC patients. The downsides of sorafenib use—high drug-related symptom burden and high drug cost—must be considered in light of this minimal benefit.

Implications for Practice:

The findings of a median survival of only 3 months in Medicare beneficiaries with HCC prescribed sorafenib as first-line therapy highlight the questionable value of sorafenib in this population. Patients should be cautioned that outside of the narrow confines of randomized trials, their life expectancy may be very short, and any benefit of sorafenib is likely to be quite small. Given that sorafenib causes considerable adverse effects and offers no symptom palliation, supportive care should be discussed as a reasonable alternative to sorafenib, particularly for patients who have a poor performance status or advanced cirrhosis.

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Metastatic Breast Cancer With ESR1 Mutation: Clinical Management Considerations From the Molecular and Precision Medicine (MAP) Tumor Board at Massachusetts General Hospital

The last decade in oncology has witnessed impressive response rates with targeted therapies, largely because of collaborative efforts at understanding tumor biology and careful patient selection based on molecular fingerprinting of the tumor. Consequently, there has been a push toward routine molecular genotyping of tumors, and large precision medicine-based clinical trials have been launched to match therapy to the molecular alteration seen in a tumor. However, selecting the "right drug" for an individual patient in clinic is a complex decision-making process, including analytical interpretation of the report, consideration of the importance of the molecular alteration in driving growth of the tumor, tumor heterogeneity, the availability of a matched targeted therapy, efficacy and toxicity considerations of the targeted therapy (compared with standard therapy), and reimbursement issues. In this article, we review the key considerations involved in clinical decision making while reviewing a molecular genotyping report. We present the case of a 67-year-old postmenopausal female with metastatic estrogen receptor-positive (ER+) breast cancer, whose tumor progressed on multiple endocrine therapies. Molecular genotyping of the metastatic lesion revealed the presence of an ESR1 mutation (encoding p.Tyr537Asn), which was absent in the primary tumor. The same ESR1 mutation was also detected in circulating tumor DNA (ctDNA) extracted from her blood. The general approach for interpretation of genotyping results, the clinical significance of the specific mutation in the particular cancer, potential strategies to target the pathway, and implications for clinical practice are reviewed in this article.

Key Points

ER+ breast tumors are known to undergo genomic evolution during treatment with the acquisition of new mutations that confer resistance to treatment.

ESR1 mutations in the ligand-binding domain of ER can lead to a ligand-independent, constitutively active form of ER and mediate resistance to aromatase inhibitors.

ESR1 mutations may be detected by genomic sequencing of tissue biopsies of the metastatic tumor or by sequencing the circulating tumor cells or tumor DNA (ctDNA).

Sequencing results may lead to a therapeutic "match" with an existing FDA-approved drug or match with an experimental agent that fits the clinical setting.

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Breast Camps for Awareness and Early Diagnosis of Breast Cancer in Countries With Limited Resources: A Multidisciplinary Model From Kenya

Background.

Breast cancer is the most common cancer of women in Kenya. There are no national breast cancer early diagnosis programs in Kenya.

Objective.

The objective was to conduct a pilot breast cancer awareness and diagnosis program at three different types of facilities in Kenya.

Methods.

This program was conducted at a not-for-profit private hospital, a faith-based public hospital, and a government public referral hospital. Women aged 15 years and older were invited. Demographic, risk factor, knowledge, attitudes, and screening practice data were collected. Breast health information was delivered, and clinical breast examinations (CBEs) were performed. When appropriate, ultrasound imaging, fine-needle aspirate (FNA) diagnoses, core biopsies, and onward referrals were provided.

Results.

A total of 1,094 women were enrolled in the three breast camps. Of those, 56% knew the symptoms and signs of breast cancer, 44% knew how breast cancer was diagnosed, 37% performed regular breast self-exams, and 7% had a mammogram or breast ultrasound in the past year. Of the 1,094 women enrolled, 246 (23%) had previously noticed a lump in their breast. A total of 157 participants (14%) had abnormal CBEs, of whom 111 had ultrasound exams, 65 had FNAs, and 18 had core biopsies. A total of 14 invasive breast cancers and 1 malignant phyllodes tumor were diagnosed

Conclusion.

Conducting a multidisciplinary breast camp awareness and early diagnosis program is feasible in different types of health facilities within a low- and middle-income country setting. This can be a model for breast cancer awareness and point-of-care diagnosis in countries with limited resources like Kenya.

Implications for Practice:

This work describes a novel breast cancer awareness and early diagnosis demonstration program in a low- and middle-income country within a limited resource setting. The program includes breast self-awareness and breast cancer education, clinical exams, and point-of-care diagnostics for women in three different types of health facilities in Kenya. This pilot program has the potential of being replicated on a national scale to create awareness about breast cancer and downstage its presentation.

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Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression

Background.

Based on the hypothesis that impaired glucose metabolism might be associated with survival outcomes independently of overt diabetes, we sought to investigate the prognostic value of routinely used glycemic parameters in a prospective study of breast cancer (BC) patients.

Patients and Methods.

Fasting blood glucose, insulin and HbA_1c levels, and insulin resistance (assessed by the Homeostasis Model Assessment [HOMA] index) at diagnosis were evaluated in 286 nondiabetic BC patients (249 with primary cancer, 37 with metastatic) with respect to those parameters' possible associations with clinicopathological features and survival outcomes. As a control group, 143 healthy women matched in a 2:1 ratio for age, blood lipid levels, and body mass index were also investigated.

Results.

Fasting blood glucose level (mean ± SD: 99 ± 26 vs. 85 ± 15 mg/dL), insulin level (median: 10.0 vs. 6.8 μIU/mL), and HOMA index (median: 2.2 vs. 1.4), but not HbA_1c level, were significantly elevated in BC patients compared with control subjects. Receiver operating characteristics analysis showed comparable areas for blood glucose and insulin levels, and HOMA index (ranging from 0.668 to 0.671). Using a cutoff level of 13 μIU/mL, insulin had the best specificity (92%) and sensitivity (41%), was significantly associated with disease stage, and acted as a negative prognostic marker of progression-free survival (hazard ratio: 2.17; 95% confidence interval: 1.13–4.20) independently of menopausal status, disease stage, hormone receptor status, and human epidermal growth factor receptor 2 and Ki67 expression.

Conclusion.

These results suggest that insulin determination might provide prognostic information in BC and support the hypothesis that lifestyle and/or pharmacological interventions targeting glucose metabolism could be considered to improve survival outcome of selected BC patients.

Implications for Practice:

Pretreatment insulin levels may represent a biomarker of adverse prognosis in nondiabetic women with breast cancer, independently of other well-established prognostic factors (i.e., stage, hormone receptors, HER2/neu, and Ki67). This finding has important implications, because it provides the rationale for lifestyle or insulin-targeting pharmacologic interventions as a means of improving breast cancer outcomes not only in early stages, but also in advanced-stage breast cancer patients with aggressive tumor phenotypes (HER2-negative hormone-resistant, or triple-negative breast cancer), in which treatments are still challenging. The possibility of using insulin as a biomarker to guide insulin-targeted interventions also should be taken into account.

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An Introduction to a Head and Neck Cancer-Specific Frailty Index and Its Clinical Implications in Elderly Patients: A Prospective Observational Study Focusing on Respiratory and Swallowing Functions

Introduction.

Frailty refers to a decreased physiologic reserve in geriatric patients and its importance in terms of treatment planning and outcome prediction has been emphasized in oncologic practices for older patients with cancer. We investigated the clinical implications of a head and neck cancer (HNC)-specific frailty index suggested by prospective clinical and functional evaluations of HNC patients.

Materials and Methods.

We analyzed data on 165 elderly patients with HNC who were prospectively enrolled in our hospital from 2010 to 2013. Pretreatment functional evaluations were performed according to all comprehensive geriatric assessment (CGA) domains. We additionally evaluated the patients' respiratory and swallowing functions using pulmonary function tests, voice handicap index (VHI), MD Anderson Dysphagia Inventory (MDADI), and other associated tests. Factors affecting the 2-year morbidity and mortality were also analyzed.

Results.

Respiratory and swallowing problems were major causes of 2-year morbidity. Pretreatment performance status, VHI ≥8, MDADI <70, dental problems, and chemotherapy were significantly associated with early morbidity and mortality (all p < .05). CGA-assessed frailty was found in 72 patients (43.6%) and was significantly associated with 2-year mortality (p = .027) but not with morbidity (p = .716). The high-risk group according to our new HNC-specific frailty index that included functional evaluations of respiration and swallowing showed significantly higher 2-year morbidity (p = .043) and mortality (p < .001).

Conclusion.

Pretreatment functional disabilities related to respiration and swallowing were significantly associated with early morbidity and mortality. The suggested index would be more useful for assessing frailty in elderly HNC patients.

Implications for Practice:

This study is the first report in terms of suggesting a new frailty index focusing on respiratory and swallowing functions in elderly patients with head and neck cancer. This study shows that functional disabilities associated with respiration and swallowing significantly affected early morbidity and mortality in these elderly patients. The head and neck cancer-specific frailty index described in this report, which includes functional evaluations of respiration and swallowing, significantly predicted both early morbidity and mortality.

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Biology and Management of Patients With Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and is associated with poor long-term outcomes compared with other breast cancer subtypes. Because of the lack of approved targeted therapy, at present chemotherapy remains the mainstay of treatment for early and advanced disease. TNBC is enriched for germline BRCA mutation, providing a foundation for the use of this as a biomarker to identify patients suitable for treatment with DNA-damaging agents. Inherited and acquired defects in homologous recombination DNA repair, a phenotype termed "BRCAness," may be present in a large proportion of TNBC cases, making it an attractive selection and response biomarker for DNA-damaging therapy. Triple-negative breast cancer is a diverse entity for which additional subclassifications are needed. Increasing understanding of biologic heterogeneity of TNBC has provided insight into identifying potentially effective systemic therapies, including cytotoxic and targeted agents. Numerous experimental approaches are under way, and several encouraging drug classes, such as immune checkpoint inhibitors, poly(ADP-ribose) polymerase inhibitors, platinum agents, phosphatidylinositol-3-kinase pathway inhibitors, and androgen receptor inhibitors, are being investigated in TNBC. Molecular biomarker-based patient selection in early-phase trials has the potential to accelerate development of effective therapies for this aggressive breast cancer subtype. TNBC is a complex disease, and it is likely that several different targeted approaches will be needed to make meaningful strides in improving the outcomes.

Implications for Practice:

Triple-negative breast cancer (TNBC) is an aggressive subtype that is associated with poor outcomes. This article reviews clinical features and discusses the molecular diversity of this unique subtype. Current treatment paradigms, the role of germline testing, and platinum agents in TNBC are reviewed. Results and observations from pertinent clinical trials with potential implications for patient management are summarized. This article also discusses the clinical development and ongoing clinical trials of novel promising therapeutic agents in TNBC.

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Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Is It a Valid Treatment Option?

Background.

Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease. Prospective clinical trials have demonstrated that lenalidomide is an effective and safe treatment option, especially for non-germinal center B-cell (non-GCB) DLBCL. However, routine clinical data are lacking, which is why we provide the results of the so-far largest relapsed/refractory (R/R) DLBCL real-life analysis.

Methods.

We retrospectively assessed 123 R/R DLBCL patients who received either 15 or 25 mg/day of lenalidomide from January 2006 to January 2015.

Results.

During a median follow-up period of 4.5 years, complete remission was achieved in 32% and a partial remission in 33% non-GCB patients compared with 0% and 3% in the GCB group (p < .001 and .001, respectively), with median response durations of 15 and 5 months, respectively (p < .001). Lenalidomide at 25 mg was superior to 15 mg in terms of response (complete remission 21% and partial remission 23% vs. 0% and 8%; p = .007 and .05) and median response duration (10 vs. 4 months; p = .03). Toxicity was limited and reversible. Median progression-free survival differed between non-GCB and GCB patients (37 vs. 30 months; p < .001) and between the two dosages (24 vs. 34 months; p = .002). However, overall survival was similar between the subgroups (38–42 months).

Conclusion.

We provide evidence that lenalidomide is a valid treatment option for R/R DLBCL, with limited and reversible toxicity, and is more efficient in non-GCB DLBCL and at higher doses.

Implications for Practice:

Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease; hence, novel therapeutic approaches are urgently needed. This study confirms that lenalidomide is a valid and well-tolerated treatment option for relapsed/refractory (R/R) DLBCL. Superior outcomes were observed in non-germinal center B-cell (GCB) DLBCL, probably because of inhibition of the nuclear factor-B pathway. Similarly, high drug doses resulted in greater clinical benefits. Overall, lenalidomide is a suitable therapeutic option for R/R DLBCL, especially in non-GCB DLBCL, and 25 mg/day dosing should be preferred.

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Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

Advances in DNA and RNA sequencing revealed substantially greater genomic complexity in breast cancer than simple models of a few driver mutations would suggest. Only very few, recurrent mutations or copy-number variations in cancer-causing genes have been identified. The two most common alterations in breast cancer are TP53 (affecting the majority of triple-negative breast cancers) and PIK3CA (affecting almost half of estrogen receptor-positive cancers) mutations, followed by a long tail of individually rare mutations affecting <1%–20% of cases. Each cancer harbors from a few dozen to a few hundred potentially high-functional impact somatic variants, along with a much larger number of potentially high-functional impact germline variants. It is likely that it is the combined effect of all genomic variations that drives the clinical behavior of a given cancer. Furthermore, entirely new classes of oncogenic events are being discovered in the noncoding areas of the genome and in noncoding RNA species driven by errors in RNA editing. In light of this complexity, it is not unexpected that, with the exception of HER2 amplification, no robust molecular predictors of benefit from targeted therapies have been identified. In this review, we summarize the current genomic portrait of breast cancer, focusing on genetic aberrations that are actively being targeted with investigational drugs.

Implications for Practice:

Next-generation sequencing is now widely available in the clinic, but interpretation of the results is challenging, and its impact on treatment selection is often limited. This work provides an overview of frequently encountered molecular abnormalities in breast cancer and discusses their potential therapeutic implications. This review emphasizes the importance of administering investigational targeted therapies, or off-label use of approved targeted drugs, in the context of a formal clinical trial or registry programs to facilitate learning about the clinical utility of tumor target profiling.

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Clinical Utility of Liquid Diagnostic Platforms in Non-Small Cell Lung Cancer

A firmer understanding of the genomic landscape of lung cancer has recently led to targeted, therapeutic advances in non-small cell lung cancer. Historically, the reference standard for the diagnosis and genetic interrogation for advanced-stage patients has been tissue acquisition via computed tomography-guided core or fine needle aspiration biopsy. However, this process can frequently put the patient at risk and remains complicated by sample availability and tumor heterogeneity. In addition, the time required to complete the diagnostic assays can negatively affect clinical care. Technological advances in recent years have led to the development of blood-based diagnostics or "liquid biopsies" with great potential to quickly diagnose and genotype lung cancer using a minimally invasive technique. Recent studies have suggested that molecular alterations identified in cell-free DNA (cfDNA) or circulating tumor DNA can serve as an accurate molecular proxy of tumor biology and reliably predict the response to tyrosine kinase therapy. In addition, several trials have demonstrated the high accuracy of microRNA (miRNA) platforms in discerning cancerous versus benign nodules in high-risk, screened patients. Despite the promise of these platforms, issues remain, including varying sensitivities and specificities between competing platforms and a lack of standardization of techniques and downstream processing. In the present report, the clinical applications of liquid biopsy technologies, including circulating tumor cells, proteomics, miRNA, and cfDNA for NSCLC, are reviewed and insight is provided into the diagnostic and therapeutic implications and challenges of these platforms.

Implications for Practice:

Although tumor biopsies remain the reference standard for the diagnosis and genotyping of non-small cell lung cancer, they remain fraught with logistical complexities that can delay treatment decisions and affect clinical care. Liquid diagnostic platforms, including cell-free DNA, proteomic signatures, RNA (mRNA and microRNA), and circulating tumor cells, have the potential to overcome many of these barriers, including rapid and accurate identification of de novo and resistant genetic alterations, real-time monitoring of treatment responses, prognosis of outcomes, and identification of minimal residual disease. The present report provides insights into new liquid diagnostic platforms in non-small cell lung cancer and discusses the promise and challenges of their current and future clinical use.

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Impact on Patient Management of [18F]-Fluorodeoxyglucose-Positron Emission Tomography (PET) Used for Cancer Diagnosis: Analysis of Data From the National Oncologic PET Registry

Introduction.

We assessed the impact of [¹⁸F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) on intended management of patients in the National Oncologic PET Registry (NOPR) for three different diagnostic indications: (a) determining whether a suspicious lesion is cancer (Dx), (b) detecting an unknown primary tumor site when there is confirmed or strongly suspected metastatic disease (cancer of unknown primary origin [CUP]), and (c) detecting a primary tumor site when there is a presumed paraneoplastic syndrome (PNS).

Methods.

We reviewed a sample of randomly selected reports of NOPR subjects who underwent PET for Dx and CUP and all reports for PNS to find subjects for analysis. For these studies, we evaluated the impact of PET on referring physicians' intended management, based on their management plans reported before and after PET.

Results.

Intended management was changed more frequently in the CUP group (43.1%) than in the Dx (23.9%) and PNS (25.4%) groups (CUP vs. Dx, p < .0001; PNS vs. Dx, p < .0001; CUP vs. PNS, p < .0002). Referring physicians reported that, in light of PET results, they were able to avoid further testing in approximately three-fourths of patients (71.8%–74.6%). At the time when the post-PET forms were completed, biopsies of suspicious sites had been performed in 21.2%, 32.4%, and 23.2%, respectively, of Dx, CUP, and PNS cases.

Conclusion.

Our analysis of NOPR data shows that PET appears to have a substantial impact on intended management when used for three common diagnostic indications.

Implications for Practice:

[¹⁸F]-fluorodeoxyglucose-positron emission tomography appears to have a substantial impact on intended management when used for three targeted diagnostic indications: (a) determining whether a suspicious lesion is cancer, (b) detecting an unknown primary tumor site in a patient with confirmed or strongly suspected metastatic disease, and (c) detecting a primary tumor site in a patient with a presumed paraneoplastic syndrome.

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Cardiogenic Shock and Respiratory Failure in a Patient With Metastatic Melanoma Receiving Trametinib Therapy

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A Randomized Phase II Study of FOLFOX With or Without the MET Inhibitor Onartuzumab in Advanced Adenocarcinoma of the Stomach and Gastroesophageal Junction

Background.

The phase II YO28252 study (NCT01590719) examined first-line onartuzumab plus mFOLFOX6 in patients with metastatic, human epidermal growth factor receptor 2-negative adenocarcinoma of the stomach or gastroesophageal junction. MET immunohistochemistry expression as a biomarker of onartuzumab activity was also examined.

Patients and Methods.

Patients were randomized 1:1 to receive standard mFOLFOX6 plus onartuzumab (10 mg/kg) or placebo in 2-week cycles for 12 cycles, followed by onartuzumab or placebo until disease progression. Coprimary endpoints were progression-free survival (PFS) in intent-to-treat (ITT) and MET-positive populations. The target hazard ratio (HR) was 0.70 for patients in the ITT group and 0.60 in the MET-positive population. Secondary endpoints were overall survival (OS), overall response rate (ORR), and safety.

Results.

Overall, 123 patients were enrolled (n = 62 onartuzumab, n = 61 placebo). Median PFS was 6.77 versus 6.97 months for onartuzumab versus placebo, respectively (HR, 1.08; 95% confidence interval [CI], 0.71–1.63; p = .71). In the MET-positive population, median PFS was 5.95 versus 6.80 months, onartuzumab versus placebo (HR, 1.38; 95% CI, 0.60–3.20; p = .45). Median OS was 10.61 months for onartuzumab versus 11.27 months for placebo) (HR, 1.06, 0.64–1.75; p = .83). In the MET-positive population, median OS was 8.51 versus 8.48 months for onartuzumab versus placebo, respectively (HR, 1.12, 95% CI, 0.45–2.78; p = .80). ORR was 60.5% for the onartuzumab group and 57.1% for placebo. Grade 3–5 adverse events (AEs) were seen in 88.3% of patients receiving onartuzumab and in 78.3% of patients receiving placebo, with serious AEs in 55% and 40%, respectively.

Conclusion.

The addition of onartuzumab to mFOLFOX6 in gastric cancer did not improve efficacy in an unselected population or in a MET immunohistochemistry-positive population.

Implications for Practice:

The YO28252 study demonstrated that the addition of the anti-MET agent onartuzumab to mFOLFOX6 for treatment of gastric cancer did not improve efficacy in an overall study population or those selected for positive MET status by immunohistochemistry. This highlights the importance of correctly selecting biomarkers for targeted therapies. A multivariate analysis suggested that MET positivity may still be prognostic for worse median overall survival in gastric cancer; therefore, it is important to continue investigation into the optimal approach to inhibit MET signaling in gastric cancer.

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Impact of Oncologists Attitudes Toward End-of-Life Care on Patients Access to Palliative Care

Background.

It is unclear how oncologists' attitudes toward end-of-life (EOL) care affect the delivery of care. The present study examined the association between oncologists' EOL care attitudes and (a) timely specialist palliative care referral, (b) provision of supportive care, and (c) EOL cancer treatment decisions.

Methods.

We randomly surveyed 240 oncology specialists at our tertiary care cancer center to assess their attitudes toward EOL care using a score derived from the Jackson et al. qualitative conceptual framework (0 = uncomfortable and 8 = highly comfortable with EOL care). We determined the association between this score and clinicians' report of specialist palliative care referral, provision of supportive care, and EOL cancer treatment decisions.

Results.

Of the 182 respondents (response rate of 76%), the median composite EOL care score was 6 (interquartile range, 5–7). A higher EOL score was significantly associated with solid tumor oncology (median 7 vs. 6 for hematologic oncology; p = .003), a greater willingness to refer patients with newly diagnosed cancer to specialist palliative care (median, 7 vs. 6; p = .01), greater comfort with symptom management (median, 6 vs. 5; p = .01), and provision of counseling (median, 7 vs. 4; p < .001) but not with cancer treatment decisions. We observed a gradient effect, with higher scores associated with a greater proportion of patients referred to palliative care (score 0–4, 27%; 5, 31%; 6, 32%; 7, 35%; and 8, 45%; p = .007).

Conclusion.

Greater comfort with EOL care was associated with higher rates of specialist palliative care referral and self-reported primary palliative care delivery. More support and education are needed for oncologists who are less comfortable with EOL care.

Implications for Practice:

In the present survey of oncology specialists, most reported that they were comfortable with end-of-life (EOL) care, which was in turn, associated with greater provision of primary palliative care and higher rates of referral to specialist palliative care. The results of the present study highlight the need for more support and education for oncologists less comfortable with EOL care because their patients might receive lower levels of both primary and secondary palliative care.

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Imagerie par tomodensitométrie du cancer bronchique non à petites cellules

Publication date: Available online 7 September 2016
Source:Cancer/Radiothérapie
Author(s): G. Chassagnon, S. Bennani, M.P. Revel
L'examen tomodensitométrique (TDM) est un élément essentiel du bilan initial des cancers bronchiques non à petites cellules. Il permet à la fois de préciser le stade de la maladie et de cibler les prélèvements histologiques et cytologiques. L'objectif de l'imagerie initiale est de préciser si la lésion est localisée, pouvant bénéficier d'un traitement local à visée curative ou s'il s'agit d'un stade avancé relevant d'un traitement médical. La tomodensitométrie thoracique est particulièrement utile pour l'évaluation de l'extension locorégionale. À l'inverse, la tomographie par émission de positrons couplée à la tomodensitométrie (TEP-TDM) est plus performante pour la recherche d'une dissémination ganglionnaire ou métastatique, en dehors de l'atteinte cérébrale. Cependant, la TEP-TDM est réservée aux patients éligibles à un traitement à visée curative au décours de la TDM initiale qui doit inclure une exploration du de l'encéphale et de l'abdomen. Les propositions pour la huitième édition de la classification TNM du cancer bronchique (2016) apportent plusieurs modifications pour le T, en renforçant notamment l'importance de la taille de la lésion. Les statuts ganglionnaires N1 et N2 sont désormais subdivisés en sous-groupes, fonctions du nombre de sites atteints.Computed tomography (CT) plays a key role in the initial evaluation of non-small cell lung cancer. It allows initial staging and helps targeting lesions for pathological analysis. The aim of initial imaging work-up is to differentiate between localized disease, eligible to a local treatment, and advanced disease requiring medical treatment. CT is very useful for the assessment of local extension but is less accurate than positron emission tomography (PET)-CT for the assessment of lymphatic and metastatic spread. However, initial staging should include CT examination of the brain and upper abdomen, and PET-CT should be only be performed in patients eligible to a local treatment after initial CT assessment. Propositions for the 8th edition of lung cancer TNM bring several changes for T staging. In particular, the weight of lesion size is increased. Similarly, N1 and N2 stages are now divided in subgroups according the number of involved stations.



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Radiothérapie conformationnelle avec modulation d’intensité des cancers des voies aérodigestives supérieures, dose de tolérance des tissus sains : appareil cochléovestibulaire et tronc cérébral

Publication date: Available online 7 September 2016
Source:Cancer/Radiothérapie
Author(s): V. Guimas, J. Thariat, P. Graff-Cailleau, P. Boisselier, Y. Pointreau, P. Pommier, X. Montbarbon, C. Laude, S. Racadot
La radiothérapie conformationnelle avec modulation d'intensité (RCMI) réduit significativement la dose reçue par l'appareil cochléovestibulaire. Cette épargne cochléovestibulaire devrait permettre une diminution de la toxicité radio-induite, notamment la surdité neurosensorielle. Cependant, l'incidence de l'hypoacousie d'intensité après RCMI est de l'ordre de 42 %. L'appareil cochléovestibulaire doit être délinéé et des contraintes de doses doivent être appliquées. Du fait de la petite taille de la cochlée, une analyse dose–volume ne peut être effectuée et les recommandations concernent seulement la dose moyenne. Les études suggèrent une toxicité cochléaire au-delà de 40Gy. Les facteurs confondants (âge, chimiothérapie concomitante, localisation et stade tumoral) doivent être pris en compte lors de la planification du traitement. L'arcthérapie volumétrique modulée (VMAT) (non coplanaire) et la tomothérapie permettraient une meilleure épargne cochléaire que la technique radiothérapie conformationnelle tridimensionnelle. L'étude de la toxicité liée à l'irradiation du tronc cérébral n'est pas aisée du fait de sa fréquence rare, de la difficulté à la distinguer d'une progression tumorale et de la description subjective de cette toxicité. La toxicité liée à l'irradiation du tronc sont la radionécrose focale du tronc, les troubles cognitifs sans démence, les lésions des nerfs crâniens, la toxicité neurologique (motrice, sensitive, vertiges). La dose maximale recommandée au niveau du tronc cérébral en fractionnement et étalement classiques est de 54Gy. Cette dose peut être dépassée très ponctuellement (volume inférieur à 10mL recevant au maximum 59Gy) à condition que le volume soit situé en périphérie du tronc.Modern techniques such as intensity modulated radiation therapy (IMRT) have been proven to significantly decrease the dose delivered to the cochleovestibular apparatus, limiting consecutive toxicity especially for sensorineural hearing loss. However, recent data still report a 42% rate of radio-induced hypoacusia underscoring the need to protect the cochleovestibular apparatus. Due to the small size of the cochlea, a precise dose–volume analysis could not be performed, and recommendations only refer to the mean dose. Confusing factors such as age, concomitant chemotherapy, primary site and tumor stage should be taken into account at the time of treatment planning. (Non-coplanar) VMAT and tomotherapy have been proven better at sparing the cochlea in comparison with 3D CRT. Brainstem radio-induced injuries were poorly studied because of their infrequency and the difficulty of distinguishing between necrosis and tumor progression in the case of a primary tumor located at the base of skull. The following toxicities have been described: brainstem focal radionecrosis, cognitive disorders without dementia, cranial nerve injuries and sensori motor disability. Maximal dose to the brainstem should be kept to < 54Gy for conventional fractionation. This dose could be exceeded (no more than 10mL should receive more than 59Gy), provided this hot spot is located in the peripheral area of the organ.



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Radiothérapie des lymphomes malins non hodgkiniens ganglionnaires folliculaires et diffus de stade limité

Publication date: Available online 7 September 2016
Source:Cancer/Radiothérapie
Author(s): C. Demoor-Goldschmidt, P. Agape, I. Barillot, M.A. Mahé
L'utilisation croissante des anticorps monoclonaux et notamment du rituximab est susceptible de faire évoluer la place de la radiothérapie dans les lymphomes malins non hodgkiniens de type B diffus à grandes cellules et folliculaires ganglionnaires localisés. À partir d'une revue de la littérature, il apparaît que la radiothérapie reste indiquée dans les formes de forte masse initiale (bulky), chez les patients en situation de réponse métabolique incomplète, les sujets âgés ayant reçu une chimiothérapie courte et ceux en situation de rechute après chimiothérapie exclusive. Dans cet article, sont également précisées les techniques de radiothérapie disponibles ainsi que les doses de radiothérapie recommandées.Treatment with monoclonal antibodies, especially rituximab, is more and more frequent and questions the interest of radiotherapy in limited stages of diffuse B-cell large cell and follicular non-Hodgkin's lymphomas. From a review of literature, it appears that radiotherapy is of interest in bulky disease, patients with incomplete metabolic response, elderly patients receiving short chemotherapy and those with recurrence after exclusive chemotherapy. Finally, this article gives recommendations on available techniques of radiotherapy and doses to be delivered.



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Audits croisés du système de management de la qualité et de la sécurité en radiothérapie : retour d’expérience et perspectives futures

Publication date: Available online 7 September 2016
Source:Cancer/Radiothérapie
Author(s): E. Leroy, A. Marque
L'audit externe du système de management de la qualité et de la sécurité en radiothérapie par des pairs, responsables qualité, réalisé par l'Association française de la qualité et sécurité en radiothérapie (AFQSR), est une opportunité d'échange sur les bonnes pratiques, les retours d'expérience, l'efficacité et les failles des dispositifs mis en place, ainsi que la perception de la qualité par l'ensemble des équipes. Nous présentons les résultats des premiers audits croisés réalisés, ainsi que les résultats d'une enquête menée sur la perception de la qualité au niveau national.The external audit of the management system of quality and safety in radiotherapy by quality managers of the French Association of Quality and Safety in Radiotherapy (AFQSR) is an opportunity to exchange good practices, returns of experience, effectiveness and weaknesses of the quality system, and its perceptions by all the teams. We present the results of the first audits conducted, and the results of a survey on the perception of quality at national level.



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Aspect méthodologique, mise en pratique et évaluation de la délégation de tâches du recalage d’images

Publication date: Available online 7 September 2016
Source:Cancer/Radiothérapie
Author(s): N. Ponsard
Mise en pratique et évaluation de la délégation de tâches du recalage d'images, l'exemple de l'habilitation des manipulateurs dans l'unité de radiothérapie du centre hospitalier de Quimper.Application and evaluation of the delegation of tasks of the recalage of images, the example of the authorization of the manipulators of the unity (unit) of radiotherapy of the Hospital center of Quimper.



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Techniques d’irradiation du cancer du sein en 2016 : intérêt et indications de la radiothérapie conformationnelle avec modulation d’intensité

Publication date: Available online 7 September 2016
Source:Cancer/Radiothérapie
Author(s): C. Bourgier, P. Fenoglietto, C. Lemanski, A. Ducteil, M. Charissoux, R. Draghici, D. Azria
Les techniques de radiothérapie des cancers du sein évoluant (tomothérapie, arcthérapie volumétrique modulée), la radiothérapie conformationnelle avec modulation d'intensité (RCMI) est de plus en plus discutée dans cette prise en charge. Nous proposons de détailler dans cette revue l'intérêt dosimétrique et clinique de la RCMI, ainsi que les indications actuellement retenues.Irradiation techniques for breast cancer (arctherapy, tomotherapy) are evolving and intensity-modulated radiation therapy is being increasingly considered for the management of these tumours. Here, we propose a review of intensity-modulated radiation therapy planning issues, clinical toxicities and indications for breast cancer.



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Quel est le rôle de la radiothérapie peropératoire dans la prise en charge du cancer du sein ?

Publication date: Available online 7 September 2016
Source:Cancer/Radiothérapie
Author(s): M. Aumont
La chirurgie conservatrice, suivie d'une radiothérapie externe mammaire, est considérée comme le traitement standard du cancer du sein localisé. Elle permet un excellent taux de contrôle local à 10ans, avec un taux de rechute de 6 %. Depuis ces dernières années l'irradiation partielle accélérée s'est développée pour réduire la durée et le volume d'irradiation. La radiothérapie peropératoire en fait partie et offre une excellente adaptation au volume cible tumoral tout en épargnant de façon importante l'irradiation des tissus sains. Cette revue a pour objectif de décrire les différentes techniques de radiothérapie peropératoire, d'en évaluer l'efficacité clinique et la tolérance, de montrer sa potentielle indication pour une population de patientes très sélectionnée et d'évoquer enfin son avenir dans le cadre de la recherche clinique.Breast-conserving surgery followed by whole breast postoperative irradiation is considered to be the current standard treatment for patients with early stage breast cancer. It allows an excellent local tumour control with 6% of local recurrence. Over the last years, partial breast radiotherapy has been developed to reduce treatment volume and duration. Intraoperative radiotherapy is one of the techniques. It offers an excellent delineation of the tumour bed and high normal tissue sparing. This purpose of this review is to describe the different intraoperative radiotherapy techniques available, to assess their potential clinical efficiency and tolerance, the recommendations for new practice with a selected population of patients and for future research.



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Radiothérapie conformationnelle des métastases osseuses vertébrales

Publication date: Available online 7 September 2016
Source:Cancer/Radiothérapie
Author(s): J.C. Faivre, J.F. Py, G. Vogin, G. Martinage, J. Salleron, P. Royer, N. Grandgirard, D. Pasquier, S. Thureau
La radiothérapie externe à visée antalgique est un standard de prise en charge des patients atteints de métastases osseuses douloureuses non compliquées et/ou dans le traitement et la prévention des complications osseuses. En cas de risque fracturaire, la radiothérapie est réalisée après une chirurgie de consolidation dans un but antalgique et de stabilisation de l'ostéosynthèse. La radiothérapie est systématique après une vertébroplastie ou une kyphoplastie. La compression médullaire est la seule indication de radiothérapie en urgence à titre exclusif en cas de non-indication chirurgicale. Elle est systématique après une chirurgie de décompression médullaire. La ré-irradiation à visée antalgique est possible en cas de réponse insuffisante ou de récidive douloureuse, en prenant en compte la dose déjà reçue aux organes à risque notamment à la moelle épinière. D'autres traitements associés, comme l'irradiation métabolique, les biphosphonates ou le denosumab, ne contre-indiquent pas la réalisation d'une radiothérapie externe à visée antalgique. Les traitements systémiques carcinologiques doivent dans la majorité des cas être suspendus, avec une période d'arrêt compte tenu du risque de radiosensibilisation ou de phénomène de rappel. Mieux encore, la radiothérapie avec modulation d'intensité et la radiothérapie en conditions stéréotaxiques peuvent s'intégrer dans une stratégie curative pour les patients atteints de cancer oligométastatique et laissent entrevoir de nouvelles perspectives de traitements.Analgesic external beam radiation therapy is a standard of care for patients with uncomplicated painful bone metastases and/or prevention of bone complications. In case of fracture risk, radiation therapy is performed after surgery in a consolidation of an analgesic purpose and stabilizing osteosynthesis. Radiotherapy is mandatory after vertebroplasty or kyphoplasty. Spinal cord compression – the only emergency in radiation therapy – is indicated postoperatively either exclusively for non surgical indication. Analgesic re-irradiation is possible in the case of insufficient response or recurrent pain after radiotherapy. Metabolic radiation, bisphosphonates or denosumab do not dissuade external radiation therapy for pain relief. Systemic oncological treatments can be suspended with a period of wash out given the risk of radiosensitization or recall phenomenon. Better yet, the intensity modulated radiotherapy and stereotactic radiotherapy can be part of a curative strategy for oligometastatic patients and suggest new treatment prospects.



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Technique d’irradiation partielle du sein : radiothérapie externe et curiethérapie

Publication date: Available online 7 September 2016
Source:Cancer/Radiothérapie
Author(s): M.-E. Chand-Fouché, D. Lam Cham Kee, M. Gautier, J.-M. Hannoun-Levi
L'expérience actuelle de l'irradiation partielle et accélérée du sein permet de distinguer au moins deux pré-requis indispensables au succès thérapeutique : le strict respect de ses indications et l'emploi d'une technique parfaitement évaluée et maîtrisée. Les techniques permettant de délivrer une irradiation partielle et accélérée du sein postopératoire sont la curiethérapie interstitielle, la curiethérapie endocavitaire et la radiothérapie externe. Après sélection appropriée des candidates, toutes les modalités d'irradiation nécessitent une définition la plus exacte possible du volume-cible et le respect de critères dosimétriques propres à chaque technique. Les données à venir des essais randomisés devraient permettre d'approfondir la connaissance de tous ces paramètres et d'apporter des réponses concernant la comparaison des différentes techniques.Accelerated Partial Breast Irradiation (APBI) appears to be an efficient therapeutic modality provided that it uses strict selection criteria and a reliable and well-managed technique. The techniques that enable to deliver postoperative APBI are interstitial brachytherapy, endocavitary brachytherapy and external beam radiation therapy. Once an appropriate selection of the candidates is made, each radiation technique needs an exact target volume definition and a strict compliance with its own dosimetric constraints. Results of ongoing randomized trials should increase our knowledge of all these parameters, and give us responses about the comparison of the different techniques.



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Radiothérapie des sarcomes des tissus mous des membres : évolution technique et impact sur le bénéfice clinique

Publication date: Available online 7 September 2016
Source:Cancer/Radiothérapie
Author(s): C. Llacer-Moscardo, C. Bourgier, A. Morel, P. Fenoglietto, S. Carrère, N. Firmin, D. Azria
Le traitement standard des sarcomes des membres repose sur l'association d'une chirurgie conservatrice et une radiothérapie. Cette stratégie permet d'optimiser le contrôle local, mais au prix d'un risque de développement de toxicité tardive liés à la radiothérapie. De ce fait, il y a un intérêt croissant à différencier les patients qui ont besoin d'une radiothérapie de ceux pour qui le taux de contrôle local est bon sans traitement complémentaire. D'autre part, la toxicité a été corrélée avec l'étendue du volume irradié et le volume exposé aux fortes doses. L'évolution technique avec le développement de la radiothérapie conformationelle avec modulation d'intensité (RCMI) guidée par l'image permet de limiter le volume irradié avec une meilleure protection des organes à risque et potentiellement un impact sur la toxicité tardive. Des efforts sont actuellement réalisés pour tenter d'améliorer le taux de contrôle local dans le sous-groupe de patients atteints de sarcome à haut risque de récidive locale. Nous discutons tous ces aspects dans cet article.The standard treatment for extremity soft tissue sarcomas is based on the association of surgery and radiotherapy. This strategy allows local control improvement with the risk of increased toxicity. There is therefore a growing interest to identify those patients who will benefit from radiotherapy and those who will have the same local control with surgery alone. Furthermore, the development of toxicity has been correlated with the extension of the irradiated volume and the volume receiving high doses. Technological development as intensity modulated radiotherapy and image-guided radiotherapy allows limited irradiated volume improving the protection of the organs at risk leading to clinical benefit improvement. Moreover, efforts are being done to improve local control for the patients at high risk of local relapse. In this paper, we discuss all these mentioned aspects.



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Indications et résultats de la protonthérapie dans le traitement des cancers

Publication date: Available online 7 September 2016
Source:Cancer/Radiothérapie
Author(s): J. Doyen, P.-Y. Bondiau, K. Benezery, J. Thariat, M. Vidal, A. Gérard, J. Hérault, C. Carrie, J.-M. Hannoun-Lévi
L'objectif de l'étude était de faire le point sur les résultats dans les principales indications de protonthérapie dans les cancers. Une revue systématique de la littérature a été réalisée par une sélection des études sur le site internet www.pubmed.com (Medline) à l'aide des mots-clés suivants : proton therapy, radiation therapy, cancer, chordoma, chondrosarcoma, uveal melanoma, retinoblastoma, meningioma, glioma, neurinoma, pituitary adenoma, medulloblastoma, ependymoma, craniopharyngioma et nasal cavity. Il existe de nombreuses études rétrospectives pour les indications classiques de protonthérapie qui sont les suivantes : tumeurs oculaires, des sinus, de la base du crâne et pédiatriques. Il n'existe toutefois aucune étude prospective, à part une de phase II dans le médulloblastome. L'utilisation de la protonthérapie dans ces indications est le fait d'un avantage dosimétrique qui prédit à doses égales avec la photonthérapie, une meilleure couverture tumorale et/ou un profil de toxicité plus favorable. En termes de contrôle tumoral, les protons sont historiquement au moins aussi efficaces que la photonthérapie, avec un profil de toxicité plus favorable prouvé pour les enfants (fonctions cognitives, fonction endocrinienne, cancers radioinduits) et un meilleur taux de contrôle tumoral pour les tumeurs des sinus du massif facial. Les avantages cliniques contrebalancent le coût de la technique dans les tumeurs pédiatriques en particulier. La protonthérapie pourrait, selon la situation, être proposée dans d'autres types de cancer. La protonthérapie a montré de bons résultats dans la prise en charge des tumeurs oculaires, des sinus de la face, des tumeurs pédiatriques, des tumeurs de la base du crâne et parachidiennes. Du fait des avantages dosimétriques de la technique, d'autres indications pourraient être posées à l'avenir.Purpose was to summarize results for proton therapy in cancer treatment. A systematic review has been done by selecting studies on the website www.pubmed.com (Medline) and using the following keywords: proton therapy, radiation therapy, cancer, chordoma, chondrosarcoma, uveal melanoma, retinoblastoma, meningioma, glioma, neurinoma, pituitary adenoma, medulloblastoma, ependymoma, craniopharyngioma and nasal cavity. There are several retrospective studies reporting results for proton therapy in cancer treatments in the following indications: ocular tumors, nasal tumors, skull-based tumors, pediatric tumors. There is no prospective study except one phase II trial in medulloblastoma. The use of proton therapy for these indications is due to dosimetric advantages offering better tumor coverage and organ at risk sparing in comparison with photon therapy. Clinical results are historically at least as efficient as photon therapy with a better toxicity profile in pediatric tumors (cognitive and endocrine functions, radiation-induced cancer) and a better tumoral control in tumors of the nasal cavity. Clinical advantages of proton therapy counterbalance its cost especially in pediatric tumors. Proton therapy could be used in other types of cancer. Proton therapy showed good outcome in ocular, nasal tumors, pediatric, skull-based and paraspinal tumors. Because of some dosimetric advantages, proton therapy could be proposed for other indications in cancer treatments.



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Development and Validation of the National Cancer Center Psychological Symptom Inventory

Abstract

Objective

To report the development and validation of the National Cancer Center Psychological Symptom Inventory (NCC-PSI).

Methods

Psychometric properties of the NCC-PSI were examined using multicenter surveys involving 400 cancer patients in five cancer-treatment hospitals throughout Korea. Related measures including The Mini International Neuropsychiatric Interview (MINI) were administered.

Results

Convergent validity was supported by NCC-PSI's significant associations with related measures. Known-group validity was proven with higher scores of helplessness/hopelessness and anxious preoccupation on the Mini-MAC in the depression and anxiety diagnosis group, defined by the NCC-PSI. Cutoff scores for insomnia, anxiety and depression were identified. Overall, the screening performance of the NCC-PSI was comparable to that of the Distress Thermometer and Patient Health Questionnare-2.

Conclusions

The NCC-PSI represents a meaningful effort to develop a distress screening tool that addresses specific psychological symptoms common in cancer, which are tailored to the local oncology care system with varying degrees of psychosocial care resources.

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