Identification of biomarkers for the prediction of radiation toxicity in prostate cancer patients

The success of radiotherapy in tumour control depends on the total dose given. However, the tolerance of the normal tissues surrounding the tumour limits this dose. It is not known why some patients develop radiation toxicity and, currently, it is not possible to predict before treatment which patients will experience adverse effects. Thus, there is an unmet clinical need for a new test to identify patients at risk of radiation toxicity. The aim of this study was to determine if spectral variations in blood lymphocytes from PCa patients may suggest Raman spectral bands that could be used in future research to identify spectral features associated with radiosensitivity. Blood samples were collected retrospectively from 42 patients enrolled on the Cancer Trials Ireland ICORG 08-17 study who had undergone radiotherapy for prostate cancer and had shown either severe or no/minimal late radiation toxicity in follow-up. Radiation response was assessed following in-vitro irradiation using Raman micro-spectroscopy in addition to the G2 chromosomal radiosensitivity assay and the γH2AX DNA damage assay. A partial least squares discriminant analysis model was developed to classify patients using known radiation toxicity scores. Following this retrospective study, blood samples were collected prospectively from 51 patients also enrolled on the ICORG 08- 17 study. These samples were collected prior to radiotherapy and these patients were categorised based on severe or no/minimal late radiation toxicity in follow-up. Radiation response was assessed following in-vitro irradiation using Raman micro-spectroscopy in addition to the G2 chromosomal radiosensitivity assay and the γH2AX DNA damage assay. A partial least squares discriminant analysis model was developed to predict radiation toxicity. Finally, blood samples were collected prospectively prior to radiotherapy from another 30 patients enrolled on the Northern Ireland Cancer Trials Centre SPORT study for prostate cancer and these patients were also categorised based on severe or no/minimal late radiation toxicity in follow-up. Radiation response was assessed following in-vitro irradiation using Raman micro-spectroscopy in addition to the citrulline assay. A partial least squares discriminant analysis model was again developed to predict radiation toxicity. Prediction of radiation toxicity outcome could not be achieved based on late radiation toxicity in the cohort of prostate cancer patients enrolled on the ICORG 08-17 study, but some success in predicting radiation toxicity could be achieved based on late radiation toxicity in the cohort of prostate cancer patients enrolled on the Northern Ireland Cancer Trials Centre SPORT study. The patients from the ICORG 08-17 study will be followed up at 6 monthly intervals until Year 9 however, and those from the SPORT study will be followed up every 6 months for up to 5 years with a minimum annual follow-up from 5- 10 years, allowing the models to be updated as patient clinical status changes. In the future, this technology may have potential to lead to individualized patient radiotherapy by identifying patients that are at risk of radiation toxicity

Clinical-laboratory portrait of patients with cervical cancer with late radiation toxicity due to radiation therapy.

According to the National Cancer Registry of Ukraine, cervical cancer ranks second among cancer morbidity, in women of reproductive age and the first place (14.1% of all cases) in the mortality from malignant neoplasms in women aged 18-29, and in aggregate almost 1.7 thousand women die from this pathology in Ukraine annually. Radiation therapy plays a leading role in the treatment of this pathology. In turn, an increase in the survival rate after the course of combined treatment leads to an increase in the absolute number of patients with adverse effects of treatment, in particular, late radiation toxicity (LRT). A retrospective analysis of 254 case histories of patients with malignant cervical neoplasms (127 patients with late radiation toxicity and 127 patients without late radiation toxicity) was conducted. Depending on the nature of the genesis of the late radiation toxicity, it has been found that inflammatory changes occurr in 95.3% of patients (atrophic cystitis, radiation recticite, radial enterocolitis, radiation retropsychoiditis, etc.); in 32,3% – late radiation toxicity of fibrotic genesis (intrapulmonary radiation, ureter stenosis, fibrosis of the skin and subcutaneous tissue of the irradiation fields, etc.); in 25.2% – degenerative late radiation toxicity (radial ulcers, fistulas, etc.) and 30.7% – hematologic late radiation toxicity. The comparative analysis of clinical and laboratory parameters of patients before and after radiotherapy with regard to cervical cancer has shown that prognostic factors of late radiation toxicity such as increase in hematocrit and fibrinogen indices deserve attention. It has also been established that the presence of laboratory signs of a cytolytic syndrome (increased levels of aspartate aminotransferase, urea and total protein) in patients with cervical cancer prior to radiation therapy can be a prerequisite for the formation of late radiation toxicity. In addition, it has been shown that the presence of concomitant aggravating diseases of the endocrine system, blood system, musculoskeletal system, nervous system and digestive system is statistically significantly (p<0,05) increases the risk of LRT in patients with cervical cancer by 20,2; 7.0; 2.3; 1.8 and 1.6 times respectively

Raman Spectroscopy of Lymphocytes for the Identification of Prostate Cancer Patients with Late Radiation Toxicity Following Radiotherapy

The success of radiotherapy in tumour control depends on the total dose given. However, the tolerance of the normal tissues surrounding the tumour limits this dose. It is not known why some patients develop radiation toxicity and, currently, it is not possible to predict before treatment which patients will experience adverse effects. Thus, there is an unmet clinical need for a new test to identify patients at risk of radiation toxicity. Here, we report a new approach based on Raman spectroscopy.Blood samples were collected from 42 patients who had undergone radiotherapy for prostate cancer and had shown either severe or no/minimal late radiation toxicity in follow up. Radiation response was assessed following in vitro irradiation using Raman spectroscopy in addition to the G2 chromosomal radiosensitivity assay and the H2AX DNA damage assay.A Partial Least Squares Discriminant Analysis model was developed to classify patients using known radiation toxicity scores. A sensitivity of 95%, specificity of 92% and overall accuracy of 93% was achieved. In the future, this technology may have potential to lead to individualised patient radiotherapy by identifying which patients are at risk of radiation toxicity

Nuclear Factor κB Inhibitors Alleviate and the Proteasome Inhibitor PS-341 Exacerbates Radiation Toxicity in Zebrafish Embryos

Inflammatory changes are a major component of the normal tissue response to ionizing radiation, and increased nuclear factor κB (NF-κB) activity is an important mediator of inflammatory responses. Here, we used zebrafish embryos to assess the capacity of two different classes of pharmacologic agents known to target NF-κB to modify radiation toxicity in the vertebrate organism. These were proteasome inhibitors, including lactacystin, MG132, and PS-341 (Bortezomib/VELCADE), and direct inhibitors of NF-κB activity, including ethyl pyruvate (EP) and the synthetic triterpenoid CDDO-TFEA (RTA401), among others. The proteasome inhibitors either did not significantly affect radiation sensitivity of zebrafish embryos (MG132, lactacystin) or rendered zebrafish embryos more sensitive to the lethal effects of ionizing radiation (PS-341). Radiosensitization by PS-341 was reduced in fish with impaired p53 expression or function but not associated with enhanced expression of select p53 target genes. In contrast, the direct NF-κB inhibitors EP and CDDO-TFEA significantly improved overall survival of lethally irradiated zebrafish embryos. In addition, direct NF-κB inhibition reduced radiation-induced apoptosis in the central nervous system, abrogated aberrations in body axis development, restored metabolization and secretion of a reporter lipid through the gastrointestinal system, and improved renal clearance compromised by radiation. In contrast to amifostine, EP and CDDO-TFEA not only protected against but also mitigated radiation toxicity when given 1 to 2 hours postexposure. Finally, four additional IκB kinase inhibitors with distinct mechanisms of action similarly improved overall survival of lethally irradiated zebrafish embryos. In conclusion, inhibitors of canonical pathways to NF-κB activation may be useful in alleviating radiation toxicity in patients. [Mol Cancer Ther 2009;8(9):2625-34] Reprinted with permission from the American Association of Cancer Research, “Nuclear factor κB inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos”, Molecular Cancer Therapy, 2009;8(9), pages 2625-2634

Can the Severity of Normal Tissue Damage after Radiation Therapy Be Predicted?

Begg discusses a new study by Svensson and colleagues in which the researchers attempted to elucidate genetic factors involved in late radiation toxicity

Analysis of Gene Expression Using Gene Sets Discriminates Cancer Patients with and without Late Radiation Toxicity

BACKGROUND: Radiation is an effective anti-cancer therapy but leads to severe late radiation toxicity in 5%–10% of patients. Assuming that genetic susceptibility impacts this risk, we hypothesized that the cellular response of normal tissue to X-rays could discriminate patients with and without late radiation toxicity. METHODS AND FINDINGS: Prostate carcinoma patients without evidence of cancer 2 y after curative radiotherapy were recruited in the study. Blood samples of 21 patients with severe late complications from radiation and 17 patients without symptoms were collected. Stimulated peripheral lymphocytes were mock-irradiated or irradiated with 2-Gy X-rays. The 24-h radiation response was analyzed by gene expression profiling and used for classification. Classification was performed either on the expression of separate genes or, to augment the classification power, on gene sets consisting of genes grouped together based on function or cellular colocalization. X-ray irradiation altered the expression of radio-responsive genes in both groups. This response was variable across individuals, and the expression of the most significant radio-responsive genes was unlinked to radiation toxicity. The classifier based on the radiation response of separate genes correctly classified 63% of the patients. The classifier based on affected gene sets improved correct classification to 86%, although on the individual level only 21/38 (55%) patients were classified with high certainty. The majority of the discriminative genes and gene sets belonged to the ubiquitin, apoptosis, and stress signaling networks. The apoptotic response appeared more pronounced in patients that did not develop toxicity. In an independent set of 12 patients, the toxicity status of eight was predicted correctly by the gene set classifier. CONCLUSIONS: Gene expression profiling succeeded to some extent in discriminating groups of patients with and without severe late radiotherapy toxicity. Moreover, the discriminative power was enhanced by assessment of functionally or structurally related gene sets. While prediction of individual response requires improvement, this study is a step forward in predicting susceptibility to late radiation toxicity

Predictive Solution for Radiation Toxicity Based on Big Data

Radiotherapy is a treatment method using radiation for cancer treatment based on a patient treatment planning for each radiotherapy machine. At this time, the dose, volume, device setting information, complication, tumor control probability, etc. are considered as a single-patient treatment for each fraction during radiotherapy process. Thus, these filed-up big data for a long time and numerous patients’ cases are inevitably suitable to produce optimal treatment and minimize the radiation toxicity and complication. Thus, we are going to handle up prostate, lung, head, and neck cancer cases using machine learning algorithm in radiation oncology. And, the promising algorithms as the support vector machine, decision tree, and neural network, etc. will be introduced in machine learning. In conclusion, we explain a predictive solution of radiation toxicity based on the big data as treatment planning decision support system

Maximum tumor diameter is associated with event-free survival in PET-negative patients with stage I/IIA Hodgkin lymphoma.

Introduction: the high cure rates achieved in early-stage (ES) Hodgkin lymphoma (HL) are one of the great successes of hemato-oncology, but late treatment-related toxicity undermines long-term survival. Improving overall survival and quality of life further will require maintaining disease control while potentially de-escalating chemotherapy and/or omitting radiotherapy to reduce late toxicity. Accurate stratification of patients is required to facilitate individualized treatment approaches. Response assessment using 18F-fluorodeoxyglucose positron emission tomography (PET) is a powerful predictor of outcome in HL,1,2 and has been used in multiple studies, including the United Kingdom National Cancer Research Institute Randomised Phase III Trial to Determine the Role of FDG–PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease (UK NCRI RAPID) trial, to investigate whether patients achieving complete metabolic remission (CMR) can be treated with chemotherapy alone.3-5 These PET-adapted trials have demonstrated that omitting radiotherapy results in higher relapse rates, but without compromising overall survival.3-5 For the 75% of patients who achieved CMR in RAPID, neither baseline clinical risk stratification (favorable/unfavorable) nor PET (Deauville score 1/2) predicted disease relapse; additional biomarkers are needed.1 Tumor bulk has long been recognized as prognostic in HL,1,6 but there remains uncertainty about the significance and definition of bulk in the era of PET-adapted treatment.7 We performed a subsidiary analysis of RAPID to assess the prognostic value of baseline maximum tumor dimension (MTD) in patients achieving CMR. Methods: ee have previously reported the RAPID trial design, primary results, and outcomes according to pretreatment risk stratification and PET score.1,3 Patients were aged 16 to 75 years with untreated ES-HL and without B-symptoms or mediastinal bulk (mass > 1/3 internal mediastinal diameter at T5/6).6 Metabolic response after 3 cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) was centrally assessed using PET (N = 562). Patients with CMR (ie, Deauville score 1-2) were randomly assigned to receive involved field radiotherapy (IFRT; n = 208) or no further therapy (NFT; n = 211). PET-positive patients (score, 3-5; n = 143) received a fourth cycle of ABVD and IFRT. Baseline disease assessment was performed by computed tomography, and bidimensional target lesion measurements were reported by local radiologists in millimeters. The association of baseline MTD with HL-related event-free survival (EFS: progression or HL-related death) and progression-free survival (PFS) (progression or any-cause death) was assessed using Kaplan-Meier and Cox regression analyses. Non-HL deaths were either related to primary treatment toxicity or occurred in HL remission.1 United Kingdom ethical approval for the RAPID trial was via the UK Multicentre Research ethics committee. Results and discussion: baseline patient characteristics have been previously described.1 Median age was 34 years (range, 16-75 years); 184 (37.4%) of 492 patients had unfavorable risk by European Organisation for Research and Treatment of Cancer criteria, and 155 (32.3%) of 480 by German Hodgkin Study Groupcriteria. Median MTD for patients achieving CMR was 3.0 cm (interquartile range, 2.0-4.0 cm) and 3.0 cm (interquartile range, 1.8-4.5 cm) in the NFT and IFRT groups, respectively, whereas PET-positive patients had a median MTD of 3.9 cm (interquartile range, 2.8-5.1 cm). After a median follow-up of 61.6 m, 44 HL progression events occurred: 21 NFT, 9 IFRT and 14 PET-positive. No patient received salvage treatment without documented progression. Only 5 HL-related deaths occurred (1 IFRT, 4 PET-positive), and 12 non-HL deaths (4 NFT, 6 IFRT, 2 PET-positive).1 For patients with CMR (N = 419), there was a strong association between MTD and EFS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.02-1.39; P = .02), adjusting for treatment group, with an approximate 19% increase in HL risk per centimeter increase in MTD. The association was similar in both treatment groups (NFT HR, 1.20 [95% CI, 0.99-1.44; P = .06]; IFRT HR, 1.19 [95% CI, 0.92-1.55; P = .19]). The observed effect sizes did not markedly change after adjusting for baseline clinical risk factors, and similar results were observed for PFS (supplemental Table 1). In contrast, for PET-positive patients, there was no association between MTD and EFS (HR, 0.88; 95% CI, 0.70-1.11; P = .29) or PFS (HR, 0.87; 95% CI, 0.70-1.08; P = .21). In an exploratory analysis within the NFT group, MTD was dichotomized using increasing 1-cm intervals to investigate the relationship between MTD thresholds and EFS. The largest effect size was observed with an MTD threshold of ≥5 cm (Table 1). Similar results were observed for PFS; this threshold also performed best in time-dependent receiver operating characteristic curve analyses. It was not possible to assess MTD thresholds in the IFRT group with only 9 events. Among all randomized patients, 79 (18.9%) had MTD of ≥5 cm, the majority with mediastinal (n = 43), supraclavicular (n = 17), or cervical (n = 16) locations. Five-year EFS for patients with MTD of ≥5 cm randomly assigned to NFT and IFRT was 79.3% (n = 39; 95% CI, 66.6%-92.0%) and 94.9% (n = 40; 95% CI, 88.0%-100%), respectively (P = .03; Figure 1)

Three-year outcomes of a once daily fractionation scheme for accelerated partial breast irradiation (APBI) using 3-D conformal radiotherapy (3D-CRT).

The aim of this study was to report 3-year outcomes of toxicity, cosmesis, and local control using a once daily fractionation scheme (49.95 Gy in 3.33 Gy once daily fractions) for accelerated partial breast irradiation (APBI) using three-dimensional conformal radiotherapy (3D-CRT). Between July 2008 and August 2010, women aged ≥40 years with ductal carcinoma in situ or node-negative invasive breast cancer ≤3 cm in diameter, treated with breast-conserving surgery achieving negative margins, were accrued to a prospective study. Women were treated with APBI using 3-5 photon beams, delivering 49.95 Gy over 15 once daily fractions over 3 weeks. Patients were assessed for toxicities, cosmesis, and local control rates before APBI and at specified time points. Thirty-four patients (mean age 60 years) with Tis 0 (n = 9) and T1N0 (n = 25) breast cancer were treated and followed up for an average of 39 months. Only 3% (1/34) patients experienced a grade 3 subcutaneous fibrosis and breast edema and 97% of the patients had good/excellent cosmetic outcome at 3 years. The 3-year rate of ipsilateral breast tumor recurrence (IBTR) was 0% while the rate of contralateral breast events was 6%. The 3-year disease-free survival (DFS), overall survival (OS), and breast cancer-specific survival (BCSS) was 94%, 100%, and 100%, respectively. Our novel accelerated partial breast fractionation scheme of 15 once daily fractions of 3.33 Gy (49.95 Gy total) is a remarkably well-tolerated regimen of 3D-CRT-based APBI. A larger cohort of patients is needed to further ascertain the toxicity of this accelerated partial breast regimen