FDG-PET imaging for radiotherapy target volume definition in lung cancer

Multimodality imaging plays a key role in the management of malignant tumours by radiation oncologists. The tumour extension at diagnosis identifies the patients in whom curative-intent radiotherapy is indicated. The target volumes and organs at risk are delineated on the relevant image modality (CT, MRI, PET), co-registered on a CT scan in treatment position for dose calculation purpose. The treatment machines are nowadays able to achieve heterogeneous dose distributions, possibly modulated within the target volume according to variations in the risk of failure. For instance, areas with high initial FDG uptake, low oxygenation, or insufficient response during radiotherapy could become the targets for selective dose increase. The scientific challenge includes registration and iterative segmentation of poorly contrasted images acquired on living bodies (variation in acquisition position, physiological movements and hollow organs filling, signal alteration induced by treatment…). The clinical validation of these innovative approaches and their diffusion in daily routine require a very close collaboration between many disciplines, based on a common language and understanding of radiotherapy target volumes, as illustrated in the present paper with FDG-PET imaging.     

Hormonal therapy combined with radiotherapy in locally advanced prostate cancer

At present radiation therapy and radical prostatectomy are considered to be the treatment of choice for clinical T1-T2 prostate cancer. In a more advanced stage of the disease (T3) 10-year overall survival is observed in approximately 40% of patients treated with conventional radiotherapy. So far only a few methods for improving the efficacy of radiotherapy have been introduced. One of them is a three-dimensional conformal radiotherapy with 3 dimensional treatment planning. These novel methods make it possible to escalate the dose to the target and protect healthy tissue at the same time. The optimal volume of irradiation, total dose, fraction dose, techniques of radiotherapy, and the end points used during the follow-up are open to debate. In recent years a few clinical trials involving hormonal therapy and radiotherapy have been carried out. The most important of these are: RTOG 8307, RTOG 8610, RTOG 9202, and EORTC 22863.In the RTOG 8307 trial the comparison of outcomes of a combined treatment with a matched-control group of patients treated by radiotherapy alone has shown that adding hormonal therapy to radiotherapy resulted in a better outcome. Another trials RTOG 8531 and RTOG 8610 produced benefit due to the implementation of hormonal therapy in radiotherapy. The EORTC trial No. 22863 showed improvement in the 5-year overall survival when hormonal therapy after the completion of radiotherapy was continued for 3 years in the investigational arm. The RTOG 9202 study indicated benefit obtained from 2 years of adjuvant hormonal therapy.The results of these trials have had a substantial impact on the management of locally advanced prostate cancer, but there are still questions that have to be answered. There is no doubt that hormonal therapy is an important component of the management of locally advanced prostate cancer. Still the optimal combination of drugs and the timing of such treatment remains controversial. Considering the potential side effects of a combined treatment on the quality of life of patients and care costs, additional properly designed randomised trials are needed to identify the subgroup of patients who will obtain the greatest benefit. Currently, it can be concluded that in the group of patients with a high risk of relapse by adding hormonal therapy to radiotherapy the outcome of treatment in patients with prostate cancer has improved.     

Radiation-induced DNA damage as a predictor of long-term toxicity in locally advanced breast cancer patients treated with high-dose hyperfractionated radical radiotherapy

This 14-year-long study makes a novel contribution to the debate on the relationship between the in vitro radiosensitivity of peripheral blood lymphocytes and normal tissue reactions after radiation therapy. The aims were (1) to prospectively assess the degree and time of onset of skin side effects in 40 prospectively recruited consecutive patients with locally advanced breast cancer treated with a hyperfractionated dose-escalation radiotherapy schedule and (2) to assess whether initial radiation-induced DNA damage in peripheral blood lymphocytes of these patients could be used to determine their likelihood of suffering severe late damage to normal tissue. Initial radiation-induced DNA double-strand breaks (DSBs) were assessed in peripheral blood lymphocytes of these patients by pulsed-field electrophoresis. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity score. A wide interindividual variation was observed in toxicity grades and in radiation-induced DNA DSBs in peripheral blood lymphocytes (mean 1.61 +/- 0.76 DSBs/Gy per 200 MBp, range 0.63- 4.08), which were not correlated. Multivariate analysis showed a correlation (P < 0.008) between late toxicity and higher prescribed protocol dose (81.6 Gy). Analysis of the 29 patients referred to 81.6 Gy revealed significantly (P < 0.031) more frequent late subcutaneous toxicity in those with intrinsic sensitivity to radiation-induced DNA DSBs of >1.69 DSBs/Gy per DNA unit. Our demonstration of a relationship between the sensitivity of in vitro-irradiated peripheral blood lymphocytes and the risk of developing late toxic effects opens up the possibility of predicting normal tissue response to radiation in individual patients, at least in high-dose non-conventional radiation therapy regimens.     

Simultaneous integrated boost radiotherapy for thyroid cancer

Aim

The purpose of this study was to examine the usefulness of using Simultaneous Integrated Boost (SIB) radiotherapy for thyroid cancer treatment.

Background

At our hospital a 3D Conformal RadioTherapy (3D-CRT) technique involving photon and electron beams for the treatment of thyroid cancer was often used.¹ High dose to the spinal canal was limiting the total dose of such a treatment. After investigation of Intensity Modulated Radiotherapy (IMRT) technique involving seven photon beams for first course of treatment³ we decided to examine possibility of reducing treatment fractions by using SIB radiotherapy.

Material and methods

Plans for 10 patients were studied. For each patient, IMRT plan for the first course of treatment (50 Gy for PTV), two plans for the second course of treatment (10 Gy for BOOST) and a SIB plan (50 Gy for PTV, 56 Gy for BOOST) were prepared. For all plans, comparisons of dose statistics for the PTV, BOOST, PTV without BOOST (defined as PTV without BOOST with 1 cm margin), spinal canal and Patient Outline (Body) was done.

Results

Minimum dose for BOOST is higher in the SIB technique than in the two course treatment. PTV without BOOST receives the same average dose in SIB and the 1st course IMRT – 50.10 Gy and 49.84 Gy, respectively. In the SIB technique, higher reduction of dose delivered to the spinal canal is possible (27 Gy compared with 30 Gy).

Conclusion

SIB therapy for thyroid cancer with relation to typical two course treatment is a good proposal of reducing the number of fractions with the same dose for BOOST and PTV without BOOST. Additionally, better sparing of the spinal canal is achieved.     

Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer

OBJECTIVES: To evaluate the efficacy and safety of combing aromatase inhibitor (AI) and cyclooxygenase-2 (COX-2) inhibitor neoadjuvantly in postmenopausal patients with invasive hormone-sensitive breast cancer. METHODS: Eighty-two patients were randomly assigned to receive exemestane 25mg daily and celecoxib 400mg twice daily (group A, n=30), exemestane 25mg daily (group B, n=24) and letrozole 2.5mg daily (group C, n=28). RESULTS: All groups showed clinical responses (58.6% for group A, 54.5% for group B and 62.0% for group C) and decrease in tumor area (61.8% for group A, 58.1% for group B and 55.7% for group C). 3 out of 5 patients with complete clinical response were observed from group A and 2 out of 69 patients operated with pathologic complete response were observed in group C. The mean microscopic tumor size was 2.53 cm for group A, 3.05 cm for group B and 2.10 cm for group C. The differences were only statistically significant when group C was compared with group B (P=0.025). The toxicity profiles among groups were satisfactory. CONCLUSION: AI is effective in treating breast cancer and may be safely used preoperatively. The addition of COX-2 inhibitor may provide additional benefit.     

Feasibility of intensity-modulated and image-guided radiotherapy for functional organ preservation in locally advanced laryngeal cancer

Purpose

The study aims to assess the feasibility of intensity-modulated and image-guided radiotherapy (IMRT, and IGRT, respectively) for functional preservation in locally advanced laryngeal cancer. A retrospective review of 27 patients undergoing concurrent chemoradiation for locally advanced laryngeal cancers (8 IMRT, 19 IGRT) was undertaken. In addition to regular clinical examinations, all patients had PET imaging at 4 months and 10 months after radiotherapy, then yearly. Loco-regional control, speech quality and feeding-tube dependency were assessed during follow-up visits.

Results

At a median follow-up of 20 months (range 6–57 months), four out of 27 patients (14.8%) developed local recurrence and underwent salvage total laryngectomy. One patient developed distant metastases following salvage surgery. Among the 23 patients who conserved their larynx with no sign of recurrence at last follow-up, 22 (95%) reported normal or near normal voice quality, allowing them to communicate adequately. Four patients (14.8%) had long-term tube feeding-dependency because of severe dysphagia (2 patients) and chronic aspiration (2 patients, with ensuing death from aspiration pneumonia in one patient).

Conclusions and Clinical Relevance

Functional laryngeal preservation is feasible with IMRT and IGRT for locally advanced laryngeal cancer. However, dysphagia and aspiration remain serious complications, due most likely to high radiation dose delivery to the pharyngeal musculatures.     

Fully automatic and robust segmentation of the clinical target volume for radiotherapy of breast cancer using big data and deep learning

PurposeTo train and evaluate a very deep dilated residual network (DD-ResNet) for fast and consistent auto-segmentation of the clinical target volume (CTV) for breast cancer (BC) radiotherapy with big data.MethodsDD-ResNet was an end-to-end model enabling fast training and testing. We used big data comprising 800 patients who underwent breast-conserving therapy for evaluation. The CTV were validated by experienced radiation oncologists. We performed a fivefold cross-validation to test the performance of the model. The segmentation accuracy was quantified by the Dice similarity coefficient (DSC) and the Hausdorff distance (HD). The performance of the proposed model was evaluated against two different deep learning models: deep dilated convolutional neural network (DDCNN) and deep deconvolutional neural network (DDNN).ResultsMean DSC values of DD-ResNet (0.91 and 0.91) were higher than the other two networks (DDCNN: 0.85 and 0.85; DDNN: 0.88 and 0.87) for both right-sided and left-sided BC. It also has smaller mean HD values of 10.5 mm and 10.7 mm compared with DDCNN (15.1 mm and 15.6 mm) and DDNN (13.5 mm and 14.1 mm). Mean segmentation time was 4 s, 21 s and 15 s per patient with DDCNN, DDNN and DD-ResNet, respectively. The DD-ResNet was also superior with regard to results in the literature.ConclusionsThe proposed method could segment the CTV accurately with acceptable time consumption. It was invariant to the body size and shape of patients and could improve the consistency of target delineation and streamline radiotherapy workflows.     

Dosimetric impact on changes in target volumes during intensity-modulated radiotherapy for nasopharyngeal carcinoma

Background and purposeTo assess anatomic changes during intensity modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) and to determine its dosimetric impact.Patients and methodsTwenty patients treated with IMRT for NPC were enrolled in this study. A second CT was performed at 38 Gy. Manual contouring of the macroscopic tumor volumes (GTV) and the planning target volumes (PTV) were done on the second CT. We recorded the volumes of the different structures, D98 %, the conformity, and the homogeneity indexes for each PTV. Volume percent changes were calculated.ResultsWe observed a significant reduction in tumor volumes (58.56 % for the GTV N and 29.52 % for the GTV T). It was accompanied by a significant decrease in the D98 % for the 3 PTV (1.4 Gy for PTV H, p = 0.007; 0.3 Gy for PTV I, p = 0.03 and 1.15 Gy for PTV L, p = 0 0.0066). In addition, we observed a significant reduction in the conformity index in the order of 0.02 (p = 0.001) and 0.01 (p = 0.007) for PTV H and PTV I, respectively. The conformity variation was not significant for PTV L. Moreover, results showed a significant increase of the homogeneity index for PTV H (+ 0.03, p = 0.04) and PTV L (+ 0.04, p = 0.01).ConclusionTumor volume reduction during the IMRT of NPC was accompanied by deterioration of the dosimetric coverage for the different target volumes. It is essential that a careful adaptation of the treatment plan be considered during therapy for selected patients.     

Effects of anastrozole on the intratumoral gene expression in locally advanced breast cancer

Intratumoral levels of E₁ (oestrone), E₁S (oestrone sulphate) and E₂ (oestradiol) are significantly reduced by treatment with the aromatase inhibitor anastrozole regardless of treatment response. The purpose of the present pilot study was to look for additional markers of biochemical response to aromatase inhibitors on mRNA expression level. Whole genome expression was studied using microarray analysis of breast cancer tissue from 12 patients with locally advanced tumors, both before and following 15 weeks of treatment with the aromatase inhibitor anastrozole (Arimidex^®). Intratumoral mRNA levels for a subset of genes coding for steroid metabolizing enzymes, hormone receptors and some growth mediators involved in cell cycle control were analysed by quantitative RT-PCR. There was a correlation between the two methods for some but not all genes. The mRNA expression levels of the different genes were correlated to each other and to the intratumoral levels of E₁, E₂ and E₁S, before and after the treatment. Notably, a correlation of the E₁/E₂ metabolic ratio to the mRNA levels of CYP19A1 was observed before treatment (r = 0.745, p < 0.005). Whole genome expression analysis of these 12 breast cancer patients revealed similar tumor classification to previously published larger studies. Tumors with no or low expression of ESR1 (oestrogen receptor) clustered together and were characterized by a strong basal-like signature highly expressing keratins 5/17, cadherin 3, frizzled and apolipoprotein D, among others. The luminal epithelial tumor cluster, on the other hand, highly expressed ESR1, GATA binding protein 3 and N-acetyl transferase. An evident ERBB2 cluster was observed due to the marked over-expression of the ERBB2 gene and GRB7 and PPARBP in this patient material). Using significance analysis of microarrays (SAM), we identified 298 genes significantly differently expressed between the partial response and progressive disease groups.     

Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer: preliminary report

Anti-aromatase therapy is important in the treatment of breast cancer in postmenopausal women. Cyclooxygenase-2 (COX-2) inhibitors have been shown to be effective in chemoprevention in animal and clinical studies. A proof of principle study was performed to investigate the efficacy of combing anti-aromatase therapy (exemestane) and COX-2 inhibitors neoadjuvantly in hormone-sensitive postmenopausal breast cancers. The initial results are reported. The patients were randomly assigned to receive exemestane 25 mg daily and celecoxib 400 mg twice daily (group A), exemestane 25 mg daily (group B) and letrozole 2.5 mg daily (group C). The analysis was based on 20 patients who received at least one cycle of treatment. Fourteen patients completed two cycles and 12 patients three cycles. All groups showed clinical response and there was decrease in tumor area in each group. However, complete clinical response was only observed for group A patients. There was also progressive decline in blood CEA and CA15.3 levels but the differences between the three groups were not significant. The results of the preliminary analysis are encouraging but definitive conclusion could only be drawn after the completion of the study.     

Advances of MUC1 as a target for breast cancer immunotherapy

MUC1 is a potential target in breast cancer immunotherapy as MUC1 is overexpressed in breast cancer, and is absent or expressed in low level in normal mammary gland. In addition, MUC1 is mostly aberrantly underglycosylated in cancer and the antigens on the cancer surface are different from normal cell. Therefore targeting MUC1 for cancer immunotherapy can exploit the difference between cancer and normal cells, and eliminating the cancerous cells while leaving the normal mammary cells unharmed. This review will focus on the recent advance of MUC1 breast cancer immunotherapy currently being investigated.     

Cytokinetic parameters of locally advanced human breast cancer treated with diethylstilbestrol and chemotherapy

Thirty-six patients with locally advanced breast cancer received diethylstilbestrol (1 mg/die) for 3 days followed by FAC (5 Fu 600 mg/m2, adriamycin 50 mg/m2, cytoxan 600 mg/m2) on day 4, q. 21 days. After three cycles, responsive patients were submitted to surgery. Tumor kinetic parameters were evaluated by TLI and PDP-LI in 22 patients on serial tumor biopsies at diagnosis (TO), after DES (T1), 24 hrs after the first FAC (T2) and at the time of radical surgery (T3). An estrogenic recruitment was evident by TLI in 9/22 tumors and by PDP-LI in 16/22 patients. Our results demonstrate that diethylstilbestrol can induce a kinetic recruitment of breast cancer cells independently from their ER content and that chemotherapy is able to stop cell proliferation.     

Mammaglobin as a potential molecular target for breast cancer drug delivery

Background

Mammaglobin (MAM) has been used as a specific molecular marker for breast cancer diagnosis. Recently, several groups of researchers proposed a number of therapeutic strategies targeting this molecule. Some of the strategies are based upon an essential but not demonstrated hypothesis – mammaglobin is associated with the surface of breast cancer cells, which strongly disputes the therapeutic strategies.

Results

We conducted a computer-based predictive analysis and identified a small fragment at the N-end of MAM as a potential transmembrane domain. We provided several evidences to demonstrate the presence of the membrane-associated MAM. We isolated the membrane protein components from known MAM positive breast cancer cells (MDA-MB361 and MDA-MB415). We showed that about 22–64% of MAM proteins, depending upon the types of the cancer cells, directly attached on the membrane of breast cancer cells, by Western blotting assays. To directly visualize the presence of the membrane-bound MAM protein, we incubated the MAM positive cancer cells with FITC labeled anti-MAM antibody, and observed clear fluorescent signals on the surface of the cells. In studying the MAM protein distribution in human breast cancer tissues, we first identified two immunostain patterns that are associated with the membrane-bound MAM: the membrane stain pattern and luminary surface stain pattern. To test whether the membrane-associated MAM can serve as a molecular target for drug delivery, we conjugated anti-MAM antibody to human low-density lipoprotein (LDL) and loaded doxorubicin (Dox) in the core of LDL. Specific binding and cytotoxicity of the MAM targeted and Dox loaded LDL was tested in the MAM positive breast cancer cells in vitro.

Conclusion

We first showed that some of MAM protein directly associated with the surface of breast cancer cells. The membrane-associated MAM protein may be utilized as a useful molecular marker for breast cancer targeted drug delivery.