Christian Thieke

Long-term survival of cancer patients compared to heart failure and stroke: A systematic review

BackgroundCancer, heart failure and stroke are among the most common causes of death worldwide. Investigation of the prognostic impact of each disease is important, especially for a better understanding of competing risks. Aim of this study is to provide an overview of long term survival of cancer, heart failure and stroke patients based on the results of large population- and hospital-based studies.MethodsRecords for our study were identified by searches of Medline via Pubmed. We focused on observed and relative age- and sex-adjusted 5-year survival rates for cancer in general and for the four most common malignancies in developed countries, i.e. lung, breast, prostate and colorectal cancer, as well as for heart failure and stroke.ResultsTwenty studies were identified and included for analysis. Five-year observed survival was about 43% for all cancer entities, 40-68% for stroke and 26-52% for heart failure. Five-year age and sex adjusted relative survival was 50-57% for all cancer entities, about 50% for stroke and about 62% for heart failure. In regard to the four most common malignancies in developed countries 5-year relative survival was 12-18% for lung cancer, 73-89% for breast cancer, 50-99% for prostate cancer and about 43-63% for colorectal cancer. Trend analysis revealed a survival improvement over the last decades.ConclusionsThe results indicate that long term survival and prognosis of cancer is not necessarily worse than that of heart failure and stroke. However, a comparison of the prognostic impact of the different diseases is limited, corroborating the necessity for further systematic investigation of competing risks.

Intensity-Modulated Radiotherapy - A Large Scale Multi-Criteria Programming Problem

Abstract. Radiation therapy planning is often a tight rope walk between dangerous insufficient dose in the target volume and life threatening overdosing of organs at risk. Finding ideal balances between these inherently contradictory goals challenges dosimetrists and physicians in their daily practice. Todays inverse planning systems calculate treatment plans based on a single evaluation function that measures the quality of a radiation treatment plan. Unfortunately, such a one dimensional approach cannot satisfactorily map the different backgrounds of physicians and the patient dependent necessities. So, too often a time consuming iterative optimization process between evaluation of the dose distribution and redefinition of the evaluation function is needed. In this paper we propose a generic multi-criteria approach based on Paretos solution concept. For each entity of interest – target volume or organ at risk – a structure dependent evaluation function is defined measuring deviations from ideal doses that are calculated from statistical functions. A reasonable bunch of clinically meaningful Pareto optimal solutions are stored in a data base, which can be interactively searched by physicians. The system guarantees dynamic planning as well as the discussion of tradeoffs between different entities. Mathematically, we model the inverse problem as a multi-criteria linear programming problem. Because of the large scale nature of the problem it is not possible to solve the problem in a 3D-setting without adaptive reduction by appropriate approximation schemes. Our approach is twofold: First, the discretization of the continuous problem results from an adaptive hierarchical clustering process which is used for a local refinement of constraints during the optimization procedure. Second, the set of Pareto optimal solutions is approximated by an adaptive grid of representatives that are found by a hybrid process of calculating extreme compromises and interpolation methods.

Correction of patient positioning errors based on in-line cone beam CTs: clinical implementation and first experiences

BackgroundThe purpose of the study was the clinical implementation of a kV cone beam CT (CBCT) for setup correction in radiotherapy.Patients and methodsFor evaluation of the setup correction workflow, six tumor patients (lung cancer, sacral chordoma, head-and-neck and paraspinal tumor, and two prostate cancer patients) were selected. All patients were treated with fractionated stereotactic radiotherapy, five of them with intensity modulated radiotherapy (IMRT). For patient fixation, a scotch cast body frame or a vacuum pillow, each in combination with a scotch cast head mask, were used. The imaging equipment, consisting of an x-ray tube and a flat panel imager (FPI), was attached to a Siemens linear accelerator according to the in-line approach, i.e. with the imaging beam mounted opposite to the treatment beam sharing the same isocenter. For dose delivery, the treatment beam has to traverse the FPI which is mounted in the accessory tray below the multi-leaf collimator. For each patient, a predefined number of imaging projections over a range of at least 200 degrees were acquired. The fast reconstruction of the 3D-CBCT dataset was done with an implementation of the Feldkamp-David-Kress (FDK) algorithm. For the registration of the treatment planning CT with the acquired CBCT, an automatic mutual information matcher and manual matching was used.Results and discussionBony landmarks were easily detected and the table shifts for correction of setup deviations could be automatically calculated in all cases. The image quality was sufficient for a visual comparison of the desired target point with the isocenter visible on the CBCT. Soft tissue contrast was problematic for the prostate of an obese patient, but good in the lung tumor case. The detected maximum setup deviation was 3 mm for patients fixated with the body frame, and 6 mm for patients positioned in the vacuum pillow. Using an action level of 2 mm translational error, a target point correction was carried out in 4 cases. The additional workload of the described workflow compared to a normal treatment fraction led to an extra time of about 10–12 minutes, which can be further reduced by streamlining the different steps.ConclusionThe cone beam CT attached to a LINAC allows the acquisition of a CT scan of the patient in treatment position directly before treatment. Its image quality is sufficient for determining target point correction vectors. With the presented workflow, a target point correction within a clinically reasonable time frame is possible. This increases the treatment precision, and potentially the complex patient fixation techniques will become dispensable.

From physical dose constraints to equivalent uniform dose constraints in inverse radiotherapy planning.

Optimization algorithms in inverse radiotherapy planning need information about the desired dose distribution. Usually the planner defines physical dose constraints for each structure of the treatment plan, either in form of minimum and maximum doses or as dose-volume constraints. The concept of equivalent uniform dose (EUD) was designed to describe dose distributions with a higher clinical relevance. In this paper, we present a method to consider the EUD as an optimization constraint by using the method of projections onto convex sets (POCS). In each iteration of the optimization loop, for the actual dose distribution of an organ that violates an EUD constraint a new dose distribution is calculated that satisfies the EUD constraint, leading to voxel-based physical dose constraints. The new dose distribution is found by projecting the current one onto the convex set of all dose distributions fulfilling the EUD constraint. The algorithm is easy to integrate into existing inverse planning systems, and it allows the planner to choose between physical and EUD constraints separately for each structure. A clinical case of a head and neck tumor is optimized using three different sets of constraints: physical constraints for all structures, physical constraints for the target and EUD constraints for the organs at risk, and EUD constraints for all structures. The results show that the POCS method converges stable and given EUD constraints are reached closely.

Evaluating target coverage and normal tissue sparing in the adjuvant radiotherapy of malignant pleural mesothelioma: Helical tomotherapy compared with step-and-shoot IMRT

PURPOSE To evaluate the potential of helical tomotherapy in the adjuvant treatment of malignant pleural mesothelioma and compare target homogeneity, conformity and normal tissue dose with step-and-shoot intensity-modulated radiotherapy. METHODS AND MATERIALS Ten patients with malignant pleural mesothelioma who had undergone neoadjuvant chemotherapy with cisplatin and permetrexed followed by extrapleural pneumonectomy (EPP) were treated in our department with 54 Gy to the hemithorax delivered by step-and-shoot IMRT. A planning comparison was performed by creating radiation plans for helical tomotherapy. The different plans were compared by analysing target homogeneity using the homogeneity indices HI(max) and HI(min) and target conformity by using the conformity index CI(95). To assess target coverage and normal tissue sparing TV(90), TV(95) and mean and maximum doses were compared. RESULTS Both modalities achieved excellent dose distributions while sparing organs at risk. Target coverage and homogeneity could be increased significantly with helical tomotherapy compared with step-and-shoot IMRT. Mean dose to the contralateral lung could be lowered beyond 5 Gy. CONCLUSIONS Our planning study showed that helical tomotherapy is an excellent option for the adjuvant intensity-modulated radiotherapy of MPM. It is capable of improving target coverage and homogeneity.

An enhanced block matching algorithm for fast elastic registration in adaptive radiotherapy

Image registration has many medical applications in diagnosis, therapy planning and therapy. Especially for time-adaptive radiotherapy, an efficient and accurate elastic registration of images acquired for treatment planning, and at the time of the actual treatment, is highly desirable. Therefore, we developed a fully automatic and fast block matching algorithm which identifies a set of anatomical landmarks in a 3D CT dataset and relocates them in another CT dataset by maximization of local correlation coefficients in the frequency domain. To transform the complete dataset, a smooth interpolation between the landmarks is calculated by modified thin-plate splines with local impact. The concept of the algorithm allows separate processing of image discontinuities like temporally changing air cavities in the intestinal track or rectum. The result is a fully transformed 3D planning dataset (planning CT as well as delineations of tumour and organs at risk) to a verification CT, allowing evaluation and, if necessary, changes of the treatment plan based on the current patient anatomy without time-consuming manual re-contouring. Typically the total calculation time is less than 5 min, which allows the use of the registration tool between acquiring the verification images and delivering the dose fraction for online corrections. We present verifications of the algorithm for five different patient datasets with different tumour locations (prostate, paraspinal and head-and-neck) by comparing the results with manually selected landmarks, visual assessment and consistency testing. It turns out that the mean error of the registration is better than the voxel resolution (2 x 2 x 3 mm(3)). In conclusion, we present an algorithm for fully automatic elastic image registration that is precise and fast enough for online corrections in an adaptive fractionated radiation treatment course.

IMRT reirradiation with concurrent cetuximab immunotherapy in recurrent head and neck cancer.

AbstractPurpose:In this retrospective investigation, the outcome and toxicity after reirradiation with concurrent cetuximab immunotherapy of recurrent head and neck cancer (HNC) in patients who had contraindications to platinum-based chemotherapy were analyzed.Materials and Methods:Ten patients with locally advanced recurrent HNC were retrospectively evaluated. In 9 cases, histology was squamous cell carcinoma, in one case adenoid cystic carcinoma. External beam radiotherapy was part of the initial treatment in all cases. Reirradiation was carried out using step-and-shoot intensity-modulated radiotherapy (IMRT) with a median dose of 50.4 Gy. Cetuximab was applied as loading dose (400 mg/m2) 1 week prior to reirradiation and then weekly concurrently with radiotherapy (250 mg/m2).Results:The median overall survival time after initiation of reirradiation was 7 months; the 1-year overall survival (OS) rate was 40%. Local failure was found in 3 patients, resulting in a 1-year local control (LC) rate of 61%. The 1-year locoregional control (LRC) rate was 44%, while the 1-year distant metastasis-free survival (DMFS) was 75%. Acute hematological toxicity was not observed in the group. Severe acute toxicity included one fatal infield arterial bleeding and one flap necrosis. Severe late toxicities were noted in 2 patients: fibrosis of the temporomandibular joint in 1 patient and stenosis of the cervical esophagus in another.Conclusions:IMRT reirradiation with concurrent cetuximab immunotherapy in recurrent HNC is feasible with acceptable acute toxicity. Further investigations are necessary to determine the clinical role of this therapy concept.ZusammenfassungZiel:In dieser Untersuchung analysierten wir Behandlungsergebnis und Toxizität nach kombinierter Re-Bestrahlung mit simultaner Cetuximab-Immuntherapie von rezidivierten HNO-Tumoren bei Patienten mit Kontraindikation gegen platinhaltige Chemotherapie.Patientengut und Methode:10 Patienten mit lokal fortgeschrittenen rezidivierten HNO-Tumoren wurden retrospektiv ausgewertet. In 9 Fällen lag histologisch ein Plattenepithelkarzinom, in einem Fall ein adenoidzystisches Karzinom vor. In jedem Fall war eine Strahlentherapie Teil des initialen Behandlungskonzeptes. Die Re-Bestrahlung wurde mittels Step-and-shoot-IMRT mit einer medianen Dosis von 50,4 Gy durchgeführt. Cetuximab wurde als „Loading Dose“ (400 mg/m2) eine Woche vor Re-Bestrahlung und danach wöchentlich simultan zur Bestrahlung (250 mg/m2) verabreicht.Ergebnisse:Das mediane Gesamtüberleben nach Re-Bestrahlung war 7 Monate; das 1-Jahres-Gesamtüberleben betrug 40%. Ein Lokalrezidiv trat bei 3 Patienten auf, was zu einer 1-Jahres-Lokalkontrolle von 61% führte. Die 1-Jahres-lokoregionäre Kontrolle betrug 44%. Das 1-Jahres-Metastasen-freie Überleben war 75% (siehe Abbildungen 1–4). Eine akute hämatologische Toxizität wurde in diesem Kollektiv nicht gesehen. Schwere Akuttoxizitäten waren eine fatale arterielle Blutung und eine Flap-Nekrose. Als schwere Spättoxizität trat eine Fibrose der Pterygiodmuskulatur bzw. des Kiefergelenks sowie eine zervikale Ösophagusstenose auf (vgl. Tabellen 2 u. 3).Schlussfolgerungen:Bei rezidivierten HNO-Tumoren ist eine IMRT-Re-Bestrahlung mit 50 Gy und simultaner Cetuximab- Immuntherapie mit einer akzeptablen Toxizität durchführbar. Es sind weitere Untersuchungen nötig, um den Stellenwert dieser Therapieform zu überprüfen.

Intensity modulated radiotherapy (IMRT) in benign giant cell tumors – a single institution case series and a short review of the literature

BackgroundGiant cell tumors are rare neoplasms, representing less than 5% of all bone tumors. The vast majority of giant cell tumors occurs in extremity sites and is treated by surgery alone. However, a small percentage occurs in pelvis, spine or skull bones, where complete resection is challenging. Radiation therapy seems to be an option in these patients, despite the lack of a generally accepted dose or fractionation concept. Here we present a series of five cases treated with high dose IMRT.Patients and MethodsFrom 2000 and 2006 a total of five patients with histologically proven benign giant cell tumors have been treated with IMRT in our institution. Two patients were male, three female, and median age was 30 years (range 20 -- 60). The tumor was located in the sacral region in four and in the sphenoid sinus in one patient. All patients had measurable gross disease prior to radiotherapy with a median size of 9 cm. All patients were treated with IMRT to a median total dose of 64 Gy (range 57.6 Gy to 66 Gy) in conventional fractionation.ResultsMedian follow up was 46 months ranging from 30 to 107 months. Overall survival was 100%. One patient developed local disease progression three months after radiotherapy and needed extensive surgical salvage. The remaining four patients have been locally controlled, resulting in a local control rate of 80%. We found no substantial tumor shrinkage after radiotherapy but in two patients morphological signs of extensive tumor necrosis were present on MRI scans. Decline of pain and/or neurological symptoms were seen in all four locally controlled patients. The patient who needed surgical salvage showed markedly reduced pain but developed functional deficits of bladder, rectum and lower extremity due to surgery. No severe acute or late toxicities attributable to radiation therapy were observed so far.ConclusionIMRT is a feasible option in giant cells tumors not amendable to complete surgical removal. In our case series local control was achieved in four out of five patients with marked symptom relief in the majority of cases. No severe toxicity was observed.

Characterization of Dose Distributions Through the Max and Mean Dose Concept

A new approach for the determination of the equivalent uniform dose (EUD) for inhomogeneously irradiated normal organs is developed and tested. The EUD is calculated as a linear combination of the maximum and the mean dose: EUD = f D max + (1- f ) D . We call this the max & mean model. The values of f are determined by a fit to the Emami tables for complication levels of 5% and 50%. The predictions of the max & mean model are compared with the Emami tables for different treatment volume fractions. The quality of the fit is also compared with the well-known power-law EUD model. The max & mean model makes it possible to make useful predictions of the EUD for organs having an organization anywhere between serial and parallel. The model can be fitted to the Emami tables within the same error range as the widely used power-law model (about 10%) and can be integrated into linear multicriteria optimization algorithms for planning of intensity-modulated radiotherapy.

Intensity modulated or fractionated stereotactic reirradiation in patients with recurrent nasopharyngeal cancer

PurposeTo report our experience with intensity-modulated or stereotactic reirradiation in patients suffering from recurrent nasopharyngeal carcinomaPatients and MethodsThe records of 17 patients with recurrent nasopharygeal carcinoma treated by intensity-modulated (n = 14) or stereotactic (n = 3) reirradiation in our institution were reviewed. Median age was 53 years and most patients (n = 14) were male. The majority of tumors showed undifferentiated histology (n = 14) and infiltration of intracranial structures (n = 12). Simultaneous systemic therapy was applied in 8 patients. Initial treatment covered the gross tumor volume with a median dose of 66 Gy (50-72 Gy) and the cervical nodal regions with a median dose of 56 Gy (50-60 Gy). Reirradiation was confined to the local relapse region with a median dose of 50.4 Gy (36-64Gy), resulting in a median cumulative dose of 112 Gy (91-134 Gy). The median time interval between initial and subsequent treatment was 52 months (6-132).ResultsThe median follow up for the entire cohort was 20 months and 31 months for survivors (10-84). Five patients (29%) developed isolated local recurrences and three patients (18%) suffered from isolated nodal recurrences. The actuarial 1- and 2-year rates of local/locoregional control were 76%/59% and 69%/52%, respectively. Six patients developed distant metastasis during the follow up period. The median actuarial overall survival for the entire cohort was 23 months, transferring into 1-, 2-, and 3-year overall survival rates of 82%, 44% and 37%. Univariate subset analyses showed significantly increased overall survival and local control for patients with less advanced rT stage, retreatment doses > 50 Gy, concurrent systemic treatment and complete response. Severe late toxicity (Grad III) attributable to reirradiation occurred in five patients (29%), particularly as hearing loss, alterations of taste/smell, cranial neuropathy, trismus and xerostomia.ConclusionReirradiation with intensity-modulated or stereotactic techniques in recurrent nasopharyngeal carcinoma is feasible and yields encouraging results in terms of local control and overall survival in patients with acceptable toxicity in patients with less advanced recurrences. However, the achievable outcome is limited in patients with involvement of intracranial structures, emphasising the need for close monitoring after primary therapy.