Prostate cancer radiation therapy: A physician’s perspective

Prostate cancer is the second most common cancer in men and a major cause of cancer deaths worldwide. Ionizing radiation has played a substantial role in the curative treatment of this disease. The historical evolution of radiotherapy techniques through 3D-conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and image-guided radiotherapy (IGRT) has allowed more accurate and precise treatments toward significant improvements in the therapeutic ratio. The addition of androgen deprivation therapy has significantly improved overall survival becoming the standard therapy for intermediate- and high-risk disease. Many randomized controlled trials have shown improved local control with dose escalation, and hypofractionated RT has been consolidated with proven efficacy and safe clinical results. However, several questions remain open in the radiotherapeutic management of prostate cancer patients and hopefully ongoing studies will shed light on these uncertainties. More individualized approaches are essential through better prognostic and novel predictive biomarkers of prostate radiotherapy response. Clinicians should critically interpret the evolving technologies in prostate cancer radiotherapy with important optimism but balancing the costs and the actual magnitude of clinical benefit. This article provides an overview of the basic aspects of radiotherapy treatment in localized prostate cancer from a physician’s perspective.     

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.     

Dosimetric evaluation study of IMRT and VMAT techniques for prostate cancer based on different multileaf collimator designs

The hypofractionated radiotherapy modality was established to reduce treatment durations and enhance therapeutic efficiency, as compared to conventional fractionation treatment. However, this modality is challenging because of rigid dosimetric constraints. This study aimed to assess the impact of multi-leaf collimator (MLC) widths (10 mm and 5 mm) on plan quality during the treatment of prostate cancer. Additionally, this study aimed to investigate the impact of the MLC mode of energy on the Agility flattening filter (FF), MLC Agility-free flattening filter (FFF), and MLCi2 for patients receiving hypofractionated radiotherapy. Two radiotherapy techniques; Intensity Modulated Radiotherapy (IMRT) and Volumetric Modulated Arc Radiotherapy (VMAT), were used in this research. In the present study, computed tomography simulations of ten patients (six plans per patient) with localized prostate adenocarcinoma were analyzed. Various dosimetric parameters were assessed, including monitor units, treatment delivery times, conformity, and homogeneity indices. To evaluate the plan quality, dose-volume histograms (DVHs) were estimated for each technique. The results demonstrated that the determined dosimetric parameters of planning target volume (PTV)p (such as D mean, conformity, and homogeneity index) showed greater improvement with MLC Agility FF and MLC Agility FFF than with MLCi2. Additionally, the treatment delivery time was reduced in the MLC Agility FF (by 31%) and MLC Agility FFF (by 10.8%) groups compared to the MLCi2 group. It is concluded that for both the VMAT and IMRT techniques, the smaller width (5 mm) MLCs revealed better planning target volume coverage, improved the dosimetric parameters for PTV, reduced the treatment time, and met the constraints for OARs. It is therefore recommended to use 5 mm MLCs for hypofractionated prostate cancer treatment due to better target coverage and better protection of OARs.

     

Breast cancer: Actual methods of treatment and future trends

The recent ten to twenty years have seen a substantial progress in the diagnosis and treatment of breast cancer. A rapid development of various curative options has led to the improvement of treatment outcomes, while paying more and more attention to the aspects of quality of life and cosmetic effect. In our publication, we wish to outline certain trends in the development of modern treatment of breast cancer. Among topics discussed are new forms of molecular diagnostics, new approach to the idea of sentinel node biopsy, as well as new techniques for delivery of medical procedures, the increasing use of nomograms, progress in the techniques of breast conservative treatment, modern approach to occult breast lesions, the increasing use of neoadjuvant treatment and intraoperative radiotherapy.     

Partial breast irradiation techniques in early breast cancer

Whole breast irradiation represents an integral part of combined breast-conserving treatment of early breast cancer. A new concept includes replacing traditionally fractionated whole breast postoperative radiotherapy by accelerated partial breast irradiation. The latter involves a variety of techniques and may be applied intraoperatively or shortly after the surgery. The intraoperative techniques include photon or electron external beam irradiation and interstitial high dose rate (HDR) brachytherapy, whereas the postoperative techniques comprise interstitial brachytherapy, be it HDR, pulse dose rate (PDR) or low dose rate (LDR), intracavitary brachytherapy and external beam radiotherapy using electrons, photons or protons. This article presents accelerated partial breast irradiation techniques, ongoing phase III trials evaluating their value and recommendations for clinical practice.     

Molecular imaging in prostate cancer

Prostate cancer (PCa) is the most common non-cutaneous malignancy in men. New ways to diagnose this cancer in its early stages are needed. Unique genetic and biochemical changes in the cell pave the way for tumors to grow and metastasize. Novel imaging approaches attempt to detect pathological processes in cancer cells at the molecular level. This has led to the establishment and development of the field of molecular imaging. Positron emission tomography (PET), magnetic resonance spectroscopic imaging (MRSI), magnetic resonance imaging (MRI), and radiolabeled antibodies are a few of the modalities that can detect abnormal tumor metabolic processes in the clinical setting. Other imaging techniques are still in their early phase of development but hold promise for the future, including bioluminescence imaging (BLI), measurement of tumor oxygenation, and measurement of uptake of iodine by tumors. These techniques are non-invasive and can spare the patient undue morbidity, while potentially providing early diagnosis, accurate follow-up and, finally, valuable prognostic information.     

Cardiac toxicity of lung cancer radiotherapy

Radical radiotherapy of lung cancer with dose escalation has been associated with increased tumor control. However, these attempts to continually improve local control through dose escalation, have met mixed results culminating in the findings of the RTOG trial 0617, where the heart dose was associated with a worse overall survival, indicating a significant contribution to radiation-induced cardiac morbidity. It is, therefore, very likely that poorly understood cardiac toxicity may have offset any potential improvement in overall survival derived from dose escalation and may be an obstacle that limits disease control and survival of patients. The manifestations of cardiac toxicity are relatively common after high dose radiotherapy of advanced lung cancers and are independently associated with both heart dose and baseline cardiac risk. Toxicity following the treatment may occur earlier than previously thought and, therefore, heart doses should be minimized. In patients with lung cancer, who not only receive substantial heart dose, but are also older with more comorbidities, all cardiac events have the potential to be clinically significant and life-threatening.Sophisticated radiation treatment planning techniques, charged particle therapy, and modern imaging methods in radiotherapy planning, may lead to reduction of the heart dose, which could potentially improve the clinical outcomes in patients with lung cancer. Efforts should be made to minimize heart radiation exposure whenever possible even at doses lower than those generally recommended. Heart doses should be limited as much as possible.A heart dosimetry as a whole is important for patient outcomes, rather than emphasizing just one parameter.     

Molecular mechanism of therapeutic approaches for human gastric cancer stem cells

Gastric cancer(GC)is a primary cause of cancer-related mortality worldwide,and even after therapeutic gastrectomy,survival rates remain poor.The presence of gastric cancer stem cells(GCSCs)is thought to be the major reason for resistance to anticancer treatment(chemotherapy or radiotherapy),and for the development of tumor recurrence,epithelial–mesenchymal transition,and metastases.Additionally,GCSCs have the capacity for self-renewal,differentiation,and tumor initiation.They also synthesize antiapoptotic factors,demonstrate higher performance of drug efflux pumps,and display cell plasticity abilities.Moreover,the tumor microenvironment(TME;tumor niche)that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor.However,the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential.In this review,we provide up-todate information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development.This information will support improved diagnosis,novel therapeutic approaches,and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy.To date,most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents.However,when used in combination with adjuvant therapy,treatment can improve.By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC,the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy,radiotherapy,or other adjuvant treatment.     

Stochastic modelling of the role of cisplatin in altered fractionation schedules for head and neck cancer

Advanced head and neck cancers are one of the most challenging cancers facing the oncologists due to their aggressiveness attributable to the high hypoxic content and the tumour's ability to repopulate during radiotherapy. Alterations of radiotherapy fractionation schedules are possible ways to improve tumour control. Clinical trials have shown that both hyperfractionated radiotherapy (multiple fractions a day, over the same treatment time), and accelerated radiotherapy (higher doses per fraction, six days a week, over 5 weeks or less) are more effective than conventional radiotherapy in the management of head and neck cancer. However, the treatment choice between hyperfractionated and accelerated radiotherapy is still debated, due to very similar results obtained regarding tumour control. Furthermore, while radiotherapy alone has an impact on the short-term prognosis of advanced head and neck cancer, the long-term benefits have been moderate. Cisplatin is a chemotherapeutic agent which combined with conventional radiotherapy has shown to improve patient survival. The present paper employs a Monte Carlo modelling approach in assessing the effect of combined cisplatin-altered fractionation schedule on tumour response. The growth of a head and neck carcinoma has been modelled using probabilistic functions sampled by computer generated random number sequences, maintaining the biological constitution of a tumour. The tumour growth model has been built to simulate the in vivo processes taking place before and after radiotherapy/chemotherapy. The model has shown that adding cisplatin to radiotherapy improves tumour control in both hyperfractionated and accelerated radiotherapy.     

Cardiotoxicity of breast cancer radiotherapy – overview of current results

Adjuvant radiotherapy after breast cancer surgery is an important part of breast cancer treatment improving local control and overall survival. However, a higher risk of cardiac mortality was observed when conventional radiotherapy techniques were used. Cardiac morbidity and mortality after radiation therapy have been studied in many meta-analyses. In those focused on modern radiotherapy techniques, cardiac morbidity and mortality were no longer presented. However, an extremely long follow-up period is required. Importantly, the cardiac morbidity rates vary depending not only on the dose delivered to the heart, but also on the systemic therapies administrated and the pre-existing cardiac disease. Systematic heart dose monitoring is of great importance, as are efforts to constantly decrease doses, using advanced radiotherapy techniques. Nowadays, it is essential to individualize treatment according to tumor characteristics and anatomical predispositions, and to consider the cost and benefits.     

Thirty-four year follow up of patients with breast cancer in clinical trial of postoperative radiotherapy.

An extended follow up to a maximum of 34 years was carried out on a series of 1461 patients who had been entered into a randomised clinical trial comparing immediate postoperative radiotherapy (treated group) with an optional delayed radiotherapy policy (watched group) after Halsted radical mastectomy for operable breast cancer. Long term survival was compared separately in patients with negative and positive axillary nodes and in two periods when different techniques of radiotherapy were used. No significant differences were noted in survival overall or in any subgroup. In patients with negative axillary nodes treated in the earlier period when the "quadrate" radiotherapy technique was used, however, the difference in survival was of borderline significance (p = 0.052), to the benefit of the watched group. Because of the large numbers of patients entered and the long follow up any possible harmful or beneficial effect of immediate postoperative radiotherapy would have been apparent in the results of this trial. The absence of any such effect implies that postoperative radiotherapy given to prevent or delay local recurrence of breast cancer is unlikely to be associated with a detectable effect on survival.     

Functions of Shp2 in cancer

Diagnostics and therapies have shown evident advances. Tumour surgery, chemotherapy and radiotherapy are the main techniques in treat cancers. Targeted therapy and drug resistance are the main focus in cancer research, but many molecular intracellular mechanisms remain unknown. Src homology region 2‐containing protein tyrosine phosphatase 2 (Shp2) is associated with breast cancer, leukaemia, lung cancer, liver cancer, gastric cancer, laryngeal cancer, oral cancer and other cancer types. Signalling pathways involving Shp2 have also been discovered. Shp2 is related to many diseases. Mutations in the ptpn11 gene cause Noonan syndrome, LEOPARD syndrome and childhood leukaemia. Shp2 is also involved in several cancer‐related processes, including cancer cell invasion and metastasis, apoptosis, DNA damage, cell proliferation, cell cycle and drug resistance. Based on the structure and function of Shp2, scientists have investigated specific mechanisms involved in cancer. Shp2 may be a potential therapeutic target because this phosphatase is implicated in many aspects. Furthermore, Shp2 inhibitors have been used in experiments to develop treatment strategies. However, conflicting results related to Shp2 functions have been presented in the literature, and such results should be resolved in future studies.     

Targeted molecular imaging of angiogenesis in PET and SPECT: a review

Over the past few decades, there have been significant advancements in the imaging techniques of positron emission tomography (PET) and single photon emission tomography (SPECT). These changes have allowed for the targeted imaging of cellular processes and the development of hybrid imaging systems (e.g., SPECT/CT and PET/CT), which provide both functional and structural images of biological systems. One area that has garnered particular attention is angiogenesis as it relates to ischemic heart disease and limb ischemia. Though the aforementioned techniques have benefits and consequences, they enable scientists and clinicians to identify regions that are vulnerable to or have been exposed to ischemic injury via non-invasive means. This literature review highlights the advancements in molecular imaging techniques and specific probes as they pertain to the process of angiogenesis in cardiovascular disease.     

Carcinoma of the Larynx: Results of Therapy

Prognosis of laryngeal carcinoma varies considerably, depending on its site and stage of development. In the past, laryngectomy was considered the treatment of choice for all but very early lesions. Results of therapy and five-year survival rates were relatively good, but the patient deprived of his larynx frequently presented difficulties in rehabilitation.Recent advances in radiotherapy techniques have permitted treatment of a greater proportion of patients with laryngeal carcinoma by this means, with encouraging results. Results of a survey in the Toronto area suggest that radiotherapy should be used as primary treatment in early and intermediate stages of the disease; radical excision combined with radiotherapy is indicated for treatment failures among early cases and for those with far-advanced disease or carcinoma outside the larynx proper. With this program five-year survival rates are comparable to those achieved when laryngectomy is the primary treatment used, and two-thirds of those who survive maintain laryngeal function.     

Role of stem cells in cancer therapy and cancer stem cells: a review

For over 30 years, stem cells have been used in the replenishment of blood and immune systems damaged by the cancer cells or during treatment of cancer by chemotherapy or radiotherapy. Apart from their use in the immuno-reconstitution, the stem cells have been reported to contribute in the tissue regeneration and as delivery vehicles in the cancer treatments. The recent concept of 'cancer stem cells' has directed scientific communities towards a different wide new area of research field and possible potential future treatment modalities for the cancer. Aim of this review is primarily focus on the recent developments in the use of the stem cells in the cancer treatments, then to discuss the cancer stem cells, now considered as backbone in the development of the cancer; and their role in carcinogenesis and their implications in the development of possible new cancer treatment options in future.     

Recommendations of the Spanish Societies of Radiation Oncology (SEOR), Nuclear Medicine & Molecular Imaging (SEMNiM), and Medical Physics (SEFM) on 18F-FDG PET-CT for radiotherapy treatment planning

Positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (FDG) is a valuable tool for diagnosing and staging malignant lesions. The fusion of PET and computed tomography (CT) yields images that contain both metabolic and morphological information, which, taken together, have improved the diagnostic precision of PET in oncology. The main imaging modality for planning radiotherapy treatment is CT. However, PET-CT is an emerging modality for use in planning treatments because it allows for more accurate treatment volume definition. The use of PET-CT for treatment planning is highly complex, and protocols and standards for its use are still being developed. It seems probable that PET-CT will eventually replace current CT-based planning methods, but this will require a full understanding of the relevant technical aspects of PET-CT planning. The aim of the present document is to review these technical aspects and to provide recommendations for clinical use of this imaging modality in the radiotherapy planning process.     

Hypofractionated radiotherapy for early breast cancer: Review of phase III studies

Breast-conserving surgery including whole breast irradiation has long been a recommended procedure for early breast cancer. However, conventionally fractionated radiotherapy requires a lengthy hospitalisation or prolonged commuting to a hospital for radiotherapy. In recent years, hypofractionated radiotherapy has increasingly been used. This method involves higher fraction doses (above 2 Gy) as compared to conventional radiotherapy, so the total dose can be delivered in fewer fractions and in a shorter overall treatment time. This review aims at presenting most important outcomes of four randomised studies comparing conventional and hypofractionated radiotherapy schemes including a total of 7000 patients. These studies have not shown apparent differences in treatment efficacy, incidence of late post-radiotherapy complications or cosmetic effects during a 5–10 year follow-up, but longer observation is warranted to fully evaluate the safety of this method. Currently, major societies consider modestly hypofractionated radiotherapy schemes as a routine management in selected groups of patients undergoing breast-conserving surgery. However, this method should be used cautiously in patients with lymph node metastases, big breasts, receiving chemotherapy or trastuzumab, or those under 50 years of age.     

Therapeutic resistance and cancer recurrence mechanisms: Unfolding the story of tumour coming back

Cancer recurrence is believed to be one of the major reasons for the failure of cancer treatment strategies. This biological phenomenon could arise from the incomplete eradication of tumour cells after chemo- and radiotherapy. Recent developments in the design of models reflecting cancer recurrence and in vivo imaging techniques have led researchers to gain a deeper and more detailed insight into the mechanisms underlying tumour relapse. Here, we provide an overview of three important drivers of recurrence including cancer stem cells (CSCs), neosis, and phoenix rising. The survival of cancer stem cells is well recognized as one of the primary causes of therapeutic resistance in malignant cells. CSCs have a relatively latent metabolism and show resistance to therapeutic agents through a variety of routes. Neosis has proven to be as an important mechanism behind tumour self-proliferation after treatment which gives rise to the expansion of tumour cells in the injured site via production of Raju cells. Phoenix rising is a pro-recurrence pathway through which apoptotic cancer cells send strong signals to the neighbouring diseased cells leading to their multiplication. The mechanisms involved in therapeutic resistance and tumour recurrence have not yet been fully understood and mostly remain unexplained. Without doubt, an improved understanding of the cellular machinery contributing to recurrence will pave the way for the development of novel, sophisticated and effective anti-tumour therapeutic strategies which can eradicate tumour without the threat of relapse.     

A realistic utilization of nanotechnology in molecular imaging and targeted radiotherapy of solid tumors

Precise dose delivery to malignant tissue in radiotherapy is of paramount importance for treatment efficacy while minimizing morbidity of surrounding normal tissues. Current conventional imaging techniques, such as magnetic resonance imaging (MRI) and computerized tomography (CT), are used to define the three-dimensional shape and volume of the tumor for radiation therapy. In many cases, these radiographic imaging (RI) techniques are ambiguous or provide limited information with regard to tumor margins and histopathology. Molecular imaging (MI) modalities, such as positron emission tomography (PET) and single photon-emission computed-tomography (SPECT) that can characterize tumor tissue, are rapidly becoming routine in radiation therapy. However, their inherent low spatial resolution impedes tumor delineation for the purposes of radiation treatment planning. This review will focus on applications of nanotechnology to synergize imaging modalities in order to accurately highlight, as well as subsequently target, tumor cells. Furthermore, using such nano-agents for imaging, simultaneous coupling of novel therapeutics including radiosensitizers can be delivered specifically to the tumor to maximize tumor cell killing while sparing normal tissue.