Topical issues in the treatment of rectal cancer: economic and organizational aspects of concomitant radiochemotherapy

Concomitant radiochemotherapy in patients with locally advanced rectal carcinoma has been shown to be useful in improving local control and survival in operated patients and in favoring sphincter preservation when administered before surgery. Together with the search for less toxic combinations, cost-analysis of radiochemotherapy has become topical also in consideration of new generation drugs. In this study the analysis was carried out by comparing the costs for 4 different combined modalities in the dual perspective of the payer (the National Health Service) and the provider (the Hospital). Based on their characteristic of treatment and innovative aspects, the following combinations were examined: external beam radiotherapy (ERT) 50.4 Gy + 5FU bolus; ERT 50.4 Gy + 5FU protracted infusion; ERT 50.4 Gy + 5FU continuous infusion, week 1 and 5; ERT 50.4 Gy+ Tomudex bolus. Costs were evaluated based on the frequency and type of specific services provided in therapeutic protocols: the positioning of central venous catheter, time of stay in day-hospital or hospital ward and the cost of drugs. Calculations were carried out based on an "ideal" patient of 1.7 sqm body surface. Costs were based on out patient rates, DRGs and the official drug list valid to September 1999. As for day-hospital costs afforded by the payer it is observed that the most expensive combinations are bolus and continuous infusion followed by protracted infusion; Tomudex, is the most economic. As for hospital costs afforded by the provider, it is observed that the most expensive combination is continuous infusion followed by protracted infusion, bolus administration and Tomudex. In conclusion, doctors are increasingly involved in the economic and organizational aspects of therapeutic decisions; however, the patient's needs should be kept in mind; apart from the therapeutic benefits, lower toxicity and ready use of treatments are amongst the patient's needs. The analysis of the patient's satisfaction is still lacking suitable means of evaluation, however it should be defined and carefully studied for an exhaustive evaluation of the impact of combined modality therapy.     

Advances in the treatment of lung cancer: economic and organizational aspects

The organizational optimization in radiotherapy tends to a correct balance of quality of service and containment of health care expenditure; this goal is necessarily correlated with the real potentialities available to each center while considering the possible clinical benefits for the patient. In lung cancer, outcomes achieved with radiation therapy are encouraging in terms of local control and survival when treatment is performed with the available modern technology whose costs from an exclusively economic analysis are shown to be still quite high. In an assessment focused on clinical outcomes, better local control, higher survival and improved quality of life represent tangible benefits: this has a positive impact on community costs and may represent a high priority goal for health care providers, yielding a benefit that can be quantified with the most recent analyses of health care economy.     

Innovative techniques in modern radiation oncology: the economic and organizational impact

An overview of the impact of innovative techniques in modern radiotherapy on economic and organizational issues is proposed. The analyzed innovative procedures are: intraoperative radiotherapy, stereotactic radiosurgery, conformal radiotherapy and high dose rate brachytherapy. They are approached separately in terms of cost-benefit analysis, optimized management and estimated productivity. The introduction of these innovative techniques in the daily practice of radiation oncology departments is vital in the quest for excellence. The strictly monetary implications of programs for the implementation of innovative radiotherapy techniques are hindered by the present planned containment of public health care expenditure in western European countries.     

The role of brachytherapy for palliation

The goal of palliative radiation is to alleviate symptoms in a short amount of time and maintain an optimal functional and quality-of-life level while minimizing toxicity and patient inconvenience. Despite advances in multimodality antineoplastic therapies, failure to control the tumor at its primary site frustratingly remains the predominant source of morbidity and mortality in many patients with cancer. Escalation of doses of radiation using external beam irradiation has been shown to improve local tumor control, but limits are imposed by the tolerance of normal surrounding structures. The highly conformal nature of brachytherapy enables the radiation oncologist to accomplish safe escalation of radiation doses to the tumor while minimizing doses to normal surrounding structures. Thus, by enhancing the potential for local control, brachytherapy used alone or as a supplement to external beam radiation therapy retains a significant and important role in achieving the goals of palliation. Proper patient selection, excellent technique, and adherence to implant rules will minimize the risk of complications. The advantages realized with the use of brachytherapy include good patient tolerance, short treatment time, and high rates of sustained palliation. This article reviews various aspects of palliative brachytherapy, including patient selection criteria, implant techniques, treatment planning, dose and fractionation schedules, results, and complications of treatment. Tumors of the head and neck, trachea and bronchi, esophagus, biliary tract, and brain, all in which local failure represents the predominant cause of morbidity and mortality, are highlighted.     

Economic and organizational aspects in the management of prostate cancer

In the last decade a rapid increase in the incidence of prostate cancer was observed. The reasons for this increase are associated to the progressive population aging, especially in the developed countries as well as to the growing number of identified cases with the widespread use of prostate specific antigen. A number of aspects of the disease are still to be considered in depth: the natural history of the disease in patients with early diagnosis, the potential costs of screening programs in financial, social and psychologic terms, the effectiveness and especially cost-effectiveness of different treatments and follow-up for local and advanced forms. Because of the long natural history of prostate cancer and the effectiveness of hormonal treatments used as salvage after failure of primary therapy, the differences in survival among the various therapeutic options, from radical prostatectomy to radiotherapy, or simple clinical control in selected cases are probably minor. This is the reason why future clinical studies should necessarily be based on multidimensional evaluations, taking into account the clinical outcome as well as the quality of life and costs of the different treatment modalities examined.     

The role of external beam in brachytherapy

In this paper we put forward the claim that the combination of low dose-rate brachytherapy (BRT) and fractionated external-beam radiotherapy (EBRT) may, when planned to take advantage of the relative advantages of each of these two modalities, result in enhanced tumor dose with no penalties to organs at risk. The concept of iso-effective dose (IED) serves the role of common currency for fusing BRT and EBRT and, for evaluation purposes, converting back the resulting IED distribution into a biologically equivalent plan delivered by any single modality. If we accept this view, there are further questions that must be answered regarding practical matters. We show how to deal with these questions by describing an actual patient plan.     

High dose rate interstitial brachytherapy in soft tissue sarcoma: technical aspects and results.

BACKGROUND: Radiation is essential for function preservation in the management of soft tissue sarcoma (STS). One of the advantages of brachytherapy is that it allows for specific localization of radiation dose to the tumor bed. We examined the results of our clinical experiences with immediate postoperative high dose rate (HDR) brachytherapy and external beam radiation treatment (EBRT) for STS. METHODS: A total of 17 patients (11 primary and six recurrent) between 1995 and 1999 were included in this review. The inclusion criteria for HDR and EBRT were as follows: (1) high-grade tumor, (2) low-grade tumor of > or = 10 cm, (3) recurrent tumor, (4) tumor abutting or invading critical structures and (5) positive margin. The catheters (six French) were placed parallel to the long axis of the tumor with a 1-1.5 cm spacing in between. If necessary, muscle or gel-foam was placed over the critical structures to maintain a minimum space of 0.5 cm from the catheters. On postoperative day 6, patients received HDR (2-3 Gy/fraction x6, twice daily). Three weeks later, patients received EBRT (total 36-60 Gy). The follow-up duration was between 13 and 60 months (median 31 months). RESULTS: There was no local failure within the radiation field in any of the patients. One patient required wound revision for delayed healing after brachytherapy. During EBRT, most patients experienced only mild erythema (grade 1 or 2 skin reaction). In long-term follow-up, there were no patients with neuropathy or significant fibrosis. CONCLUSIONS: Our results suggest that immediate postoperative HDR with a total dose of 12-18 Gy over 3 days is an effective treatment combined with EBRT in the management of STS.     

Interstitial multi-catheter breast brachytherapy: Technical aspects and experience feedback in a comprehensive cancer center

PurposeTo focus on technical aspects of the implementation of interstitial high dose rate brachytherapy, with a step-by-step approach.Materials and methodsPatients were selected during multidisciplinary tumor boards, according to inclusion criteria adapted from GEC-ESTRO guidelines. A CT scan was performed a few days before implantation. On pre-implant CT, using surgical scar and clips, surgical and pathological reports, and preoperative images, we delineated the tumor bed to be included in the Clinical Target Volume (CTV), according to GEC ESTRO Recommendations. A 3D virtual implant simulation of the best catheter positions was performed in order to cover the target volume. Implantation was then carried out under local anaesthetic using 3D projections of the catheter inlets and outlets. Dosimetry was performed on post-implantation CT scan. A dose of 34 Gy was delivered in 10 fractions. Acute and late side effects, and local control were evaluated 2 and 8 months after treatment.ResultsBetween July 2017 and January 2020, 20 patients were treated with accelerated partial breast irradiation. Dose constraints regarding target volume coverage, overdose, dose homogeneity, conformation index and organs at risk were met in 94.7%, 100%, 63.2%, 0% and 89.5% of the treatment plans, respectively. Grade 1-2 acute adverse events were observed in 21% of patients, with no grade 3-4 events.ConclusionThe first dosimetric results and early clinical tolerance and efficacy achieved by the implementation of breast interstitial multicatheter brachytherapy in routine clinical practice are very encouraging, and confirm the interest of extending this practice.     

High dose-rate brachytherapy of prostate cancer utilising Iridium-192 after-loading technique: technical and methodological aspects

The aim of this study was to focus on certain characteristic problems associated with Iridium-192 high dose-rate brachytherapy (Ir-192 HDR-BT) in combination with external beam radiation therapy (EBRT) in the treatment of patients with localised prostate cancer. Over a period of 16 years, >2,000 patients with prostate cancer have been treated in Sweden with a combination of two fractions of 10 Gy Ir-192 HDR-BT and 50 Gy of fractionated EBRT. Although this treatment is usually well tolerated, there are biological and technical factors to be considered before and during the treatment of the patient to avoid side effects or under-treatment of the target volume. Some of the problems facing the doctors are transducer stability, needle deviation, target definition, target motion, pubic arch interference, concomitant diseases and tolerance doses for different organs at risk. These problems are discussed and possible solutions are presented in this study.     

The role of brachytherapy in early-stage nasopharyngeal carcinoma

To present the treatment results and assess the optimal radiation dose and the role of brachytherapy in early stage nasopharyngeal cancer (NPC).

One hundred eighty-three patients with Stage I and II (American Joint Committee on Cancer Staging System, 1987) NPC completed the planned radiotherapy in our institution from 1979 to 1991. In 133 patients, radiotherapy was given to the nasopharynx by external beam to 64.8–68.4 Gy. Further boost was done by high dose rate (HDR) brachytherapy for 5–16.5 Gy in one to three fractions. For the remaining 50 patients, a course of external radiotherapy to the nasopharynx for 68.4–72 Gy was given to nasopharynx. Age (>40 or not) sex, neck boost or not, brachytherapy, and irradiation dose were analyzed to determine significant factors that influence the probabilities of local control and actuarial survival.

The 5-year disease-specific survival was 85.8% and local control was 83%. Only the brachytherapy and irradiation dose significantly affected the results. The use of the brachytherapy had significant impact on overall survival and local control. Furthermore, we compared the prognostic effect of various radiation dosage among Group I of 50 patients (<72.5 Gy, no brachytherapy, excluding four patients who received brachytherapy), Group II of 71 patients (72.5–75 Gy; one to two fractions of brachytherapy), and Group III of 58 patients (>75 Gy; three fractions of brachytherapy). Five-year disease-specific survival rates of Group I, Group II, and Group III were 77, 95.5, and 82.4%, respectively. Five-year local control rates were: 73.7, 93.9, and 79.5%. We found that the Group II had the best actuarial survival and local control rate (log-rank test, p < 0.05). Most patients receiving brachytherapy encountered foul odor because of nasopharynx crust; 12 of them had palate or sphenoid sinus floor perforation or nasopharynx necrosis. None of the patients without brachytherapy experienced the same complications.

The optimal radiotherapy dose to the nasopharnyx area in early stage NPC may be within 72.5 to 75 Gy by our treatment protocol. A dose of more than 75 Gy did not have significant local control or survival advantage. The use of brachytherapy to elevate radiation dose had significant local control and survival benefit for early stage NPC patients, but the fractionation size should be decreased to reduce the complications.     

Safety aspects of pulsed dose rate brachytherapy: analysis of errors in 1,300 treatment sessions

PURPOSE: To determine the safety of pulsed-dose-rate (PDR) brachytherapy by analyzing errors and technical failures during treatment. METHODS AND MATERIALS: More than 1,300 patients underwent treatment with PDR brachytherapy, using five PDR remote afterloaders. Most patients were treated with consecutive pulse schemes, also outside regular office hours. Tumors were located in the breast, esophagus, prostate, bladder, gynecology, anus/rectum, orbit, head/neck, with a miscellaneous group of small numbers, such as the lip, nose, and bile duct. Errors and technical failures were analyzed for 1,300 treatment sessions, for which nearly 20,000 pulses were delivered. For each tumor localization, the number and type of occurring errors were determined, as were which localizations were more error prone than others. RESULTS: By routinely using the built-in dummy check source, only 0.2% of all pulses showed an error during the phase of the pulse when the active source was outside the afterloader. Localizations treated using flexible catheters had greater error frequencies than those treated with straight needles or rigid applicators. Disturbed pulse frequencies were in the range of 0.6% for the anus/rectum on a classic version 1 afterloader to 14.9% for orbital tumors using a version 2 afterloader. Exceeding the planned overall treatment time by >10% was observed in only 1% of all treatments. Patients received their dose as originally planned in 98% of all treatments. CONCLUSIONS: According to the experience in our institute with 1,300 PDR treatments, we found that PDR is a safe brachytherapy treatment modality, both during and outside of office hours.     

Myelodysplastic syndromes: aspects of current medical care and economic considerations in Germany

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases mainly affecting older people. The use of an increasing number of therapeutic options depends on a systematic risk stratification of the patients. A high percentage of MDS patients need blood transfusions as supportive care, which influence quality of life and cause a great part of the costs generated by MDS therapy. In this article which is based on a workshop about the burden of MDS held in October 2006 in Munich, MDS is discussed with regard to different aspects: current therapies, transfusion medicine, geriatrics, quality of life, and health economic aspects.     

Radiation therapy of esophageal cancer: role of high dose rate brachytherapy.

Fifty untreated cases of squamous cell carcinoma arising from the middle one-third of the esophagus, with no apparent extraesophageal spread on a computed tomography (CT) scan and with a Karnofsky performance status of over 70, were treated by external beam irradiation to a dose of 3500 cGy/15 fractions/3 weeks. Twenty-five patients (Group A) received treatment with further external beam irradiation to a dose of 2000 cGy/10 fractions/2 weeks. Another group of 25 patients (Group B) received treatment with high dose rate intracavitary irradiation to a dose of 1200 cGy delivered in two sessions of 600 cGy each a week apart. All patients were assessed symptomatically, endoscopically, and radiologically every 3 months. There was marked difference at the end of 1 year in relief of dysphagia (37.5% in Group A vs. 70.6% in Group B), local control (25% in group A vs. 70.6% in group B) although the results were statistically insignificant (p greater than 0.05) and actuarial survival (44% in group A vs. 78% in group B) which was, however, significant statistically (z = 2.83). The cumulative radiation effect (CRE) by external beam irradiation was 1729 reu and by external beam and intracavitary irradiation 1741 reu, but the biological dose effect was better with external beam and intracavitary irradiation. Eight percent of patients treated by external beam and intracavitary irradiation had strictures in contrast to 4% treated by external beam irradiation alone. Moderate doses of external beam and intracavitary irradiation can give a better local response than external beam irradiation alone for the same biological dose in the treatment of esophageal carcinoma.     

The emerging role of high-dose-rate brachytherapy for prostate cancer

By placing radioactive sources directly into the cancer, brachytherapy allows delivery of a highly conformal radiation dose to the prostate. Permanent seed brachytherapy is most commonly used for low-risk cancer, whereas high-dose-rate (HDR) brachytherapy is combined with external-beam radiotherapy to treat higher risk disease. The high rate of dose delivery and the large fraction size may be a radiobiological advantage for tumours with high sensitivity to radiation fraction size. The ability to optimise dose delivery allows for exquisite shaping of dose around the prostate and sparing of normal tissues. HDR brachytherapy is most commonly delivered in two or more fractions of 810 Gy combined with 40-50 Gy external beam. Published studies are almost entirely limited to single-institution case series. Most of the patients treated have relatively unfavourable localised disease, with a reported disease-free survival of 68-93%, and a local control rate of over 90%. Treatment is well tolerated, with urethral stricture the most common late effect (risk around 8%). Early results using HDR monotherapy in low-risk disease seem promising. Patients most likely to benefit from a combined HDR/external-beam approach have bulky local disease (stage T2b-T3) or intermediate to high-grade cancers. Prospective multicentre studies of HDR brachytherapy have begun in this patient group in Canada and the USA, which hopefully will allow future comparisons with high-dose conformal external-beam techniques.     

Indications and technical aspects of brachytherapy in breast conserving treatment of breast cancer.

Improved local control rates have been demonstrated in retrospective studies as well as in randomised trials on brachytherapy with increasing doses to the tumour bed. The higher local control obtained by interstitial breast implants, as compared to external photon or electron beam boosts, have been mainly attributed to the higher doses actually delivered to the tumour bed by these implants for the same nominal dose as compared to external beam radiotherapy (RT). On the other hand, poor cosmesis has also been correlated with radiation dose to the breast skin (radiation teleangiectases), and breast tissue (retraction due to fibrosis), the latter depending not only on RT dose but also on the treated boost volume. For this reason, a possible benefit of interstitial implants will only be realized when the gain in local control goes together with minimal cosmetic damage. Therefore, the ballistic advantages of interstitial implants have to be maximally exploited: i.e. the treated volume should be maximally adapted to the target volume, and additional irradiation of the breast skin by the boost technique should be avoided. This paper deals in detail with the technical aspects of breast brachytherapy that seem to be relevant for high quality outcome.     

125I interstitial brachytherapy for primary malignant brain tumors: technical aspects of treatment planning and implantation methods

Use of interstitial radiation holds promise in the treatment of primary malignant brain tumors, but optimal technical factors have yet to be determined. We have developed a method of precise CT directed stereotactic placement of radioactive sources in a predetermined target volume. We use low activity (1-2 millicurie/speed) sources of 125I loaded in silastic catheters, which are positioned in a parallel array in the target. Positioning of such multiple sources toward the periphery of the volume enhances achievable dose homogeneity. Seeds of various activities can be differentially loaded into each catheter and the catheters can be positioned at various radii from the central target so that the treated volume corresponds to the identified (often irregular) target volume. Although the implant is designed to be permanent, the sources can be removed easily in a second procedure.     

Hematological malignancies: role of miRNAs and their in silico aspects

Hematological malignancies is a broad term that includes blood cell cancers including chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), Myelodysplastic syndrome, acute lymphocytic leukemia (ALL), multiple myelomas (MM) and lymphomas. miRNAs are ~22-nt long non-coding RNAs that play a very important role in gene regulation by binding to mRNA at their complementary sequence. These miRNAs are conceptually connected with various signal and pathway networks that make them capable of regulating various diseases including hematological malignancies. These miRNAs are not only playing regulatory roles in hematological malignancies, but are also providing new potent markers for efficient diagnosis and prognosis for hematological malignancies patients. Since the discovery of very first miRNA, the importance and role of miRNAs have been established in various fields, and there is a need to search for new potent miRNAs and their targets. A large amount of sequence data have been generated in last few years, which has further generated the need to develop efficient and reliable computational tools to analyze and extract out relevant information promptly from raw data. Here, we review various possible roles played by miRNA in hematological malignancies, principles involved in miRNA gene identification, target prediction and their preceding role in hematological malignancies research.