Combined wIRA-Hyperthermia and Hypofractionated Re-Irradiation in the Treatment of Locally Recurrent Breast Cancer: Evaluation of Therapeutic Outcome Based on a Novel Size Classification.

Effective tumor control in patients suffering from unresectable locally recurrent breast cancer (LRBC) in pre-irradiated areas can be achieved by re-irradiation combined with superficial hyperthermia. Using this combined modality, total re-irradiation dose and toxicity can be significantly reduced compared to conventionally fractionated treatment schedules with total doses of 60-66 Gy. Applying contact-free, thermography-controlled water-filtered infrared-A superficial hyperthermia, immediately followed by hypofractionated re-irradiation, consisting of 4 Gy once per week up to a total dose of 20 Gy, resulted in high overall response rates even in large-sized tumors. Comparability of clinical data between different combined Hyperthermia (HT)/Radiotherapy (RT) treatment schedules is impeded by the highly individual characteristics of this disease. Tumor size, ranging from microscopic disease and small lesions to large-sized cancer en cuirasse, is described as one of the most important prognostic factors. However, in clinical studies and analyses of LRBC, tumor size has so far been reported in a very heterogeneous way. Therefore, we suggest a novel, simple and feasible size classification (rClasses 0-IV). Applying this classification for the evaluation of 201 patients with pre-irradiated LRBC allowed for a stratification into distinct prognostic groups.

Elective Node Irradiation With Integrated Boost to the Prostate Using Helical IMRT-Clinical Outcome of the Prospective PLATIN-1 Trial.

Introduction: This prospective, non-randomized phase II trial aimed to investigate the role of additional irradiation of the pelvic nodes for patients with prostate cancer and a high risk for nodal metastases using helical intensity-modulated radiotherapy with daily image guidance (IMRT/IGRT). Methods and materials: Between 2009 and 2012, 40 men with treatment-naïve prostate cancer and a risk of lymph node involvement of more than 20% were enrolled in the PLATIN-1 trial. All patients received definitive, helical IMRT of the pelvic nodes (total dose of 51.0 Gy) with a simultaneous integrated boost (SIB) to the prostate (total dose of 76.5 Gy) in 34 fractions. Antihormonal therapy (AHT) was administered for a minimum of 2 months before radiotherapy continuing for at least 24 months. Results: After a median follow-up of 71 months (range: 5-95 months), pelvic irradiation was associated with a 5-year overall survival (OS) and biochemical progression-free survival (bPFS) of 94.3% and 83.6%, respectively. For our cohort, no grade 4 gastrointestinal (GI) and genitourinary (GU) toxicity was observed. Quality of life (QoL) assessed by EORTC QLQ-C30 questionnaire was comparable to EORTC reference values without significant changes. Conclusion: The current trial demonstrates that elective IMRT/IGRT of the pelvic nodes with SIB to the prostate for patients with a high-risk of lymphatic spread is safe and shows an excellent clinical outcome without compromising the quality of life. The PLATIN-1 trial delivers eminent baseline data for future studies using modern irradiation techniques.

Whole-brain helical tomotherapy with integrated boost for brain metastases in patients with malignant melanoma - final results of the BRAIN-RT trial.

Background: Patients with multiple brain metastases (BMs) from malignant melanoma have a poor prognosis. Recent developments in radiation techniques allow simultaneous integrated boost (SIB) concepts while sparing organs at risk. Data on conventional versus dose-escalated radiation approaches in multiple BMs from malignant melanoma are warranted. Methods: In this prospective, single-center, randomized two-armed study (trial ID: DRKS00005127), patients with multiple BMs from malignant melanoma were treated with either conventional whole-brain radiotherapy (WBRT) applying 30 Gy in 10 fractions (standard arm) or helical tomotherapy applying 30 Gy to the whole brain with an integrated boost to metastases of 50 Gy in 10 fractions and sparing of the hippocampus (HA-WBRT, experimental arm). The primary endpoint was treatment-related toxicity, while secondary endpoints were imaging response, intracerebral progression-free survival (PFS), overall survival (OS) and quality of life. Results: The study was stopped early due to slow patient recruitment. A total number of 7 patients were enrolled (standard arm n=3, experimental arm n=4), and were followed-up for a median time of 5 months between August 2013 and July 2017. All patients were treated according to protocol. The median OS, intracerebral PFS and follow-up time were 5 months, 2 months and 5 months, respectively. The local control in every individual BM was significantly longer in the experimental versus the standard arm. No patient developed radiation-related high-grade toxicities. Conclusion: HA-WBRT with SIB results in improved local control in the individual melanoma BMs without radiation-associated high-grade toxicities. Survival times were comparable to published data.

Interfraction variation and dosimetric changes during image-guided radiation therapy in prostate cancer patients.

PURPOSE: The aim of this study was to identify volume changes and dose variations of rectum and bladder during radiation therapy in prostate cancer (PC) patients. MATERIALS AND METHODS: We analyzed 20 patients with PC treated with helical tomotherapy. Daily image guidance was performed. We re-contoured the entire bladder and rectum including its contents as well as the organ walls on megavoltage computed tomography once a week. Dose variations were analyzed by means of Dmedian, Dmean, Dmax, V10 to V75, as well as the organs at risk (OAR) volume. Further, we investigated the correlation between volume changes and changes in Dmean of OAR. RESULTS: During treatment, the rectal volume ranged from 62% to 223% of its initial volume, the bladder volume from 22% to 375%. The average Dmean ranged from 87% to 118% for the rectum and 58% to 160% for the bladder. The Pearson correlation coefficients between volume changes and corresponding changes in Dmean were -0.82 for the bladder and 0.52 for the rectum. The comparison of the dose wall histogram (DWH) and the dose volume histogram (DVH) showed that the DVH underestimates the percentage of the rectal and bladder volume exposed to the high dose region. CONCLUSION: Relevant variations in the volume of OAR and corresponding dose variations can be observed. For the bladder, an increase in the volume generally leads to lower doses; for the rectum, the correlation is weaker. Having demonstrated remarkable differences in the dose distribution of the DWH and the DVH, the use of DWHs should be considered.

Helical tomotherapy in patients with leptomeningeal metastases.

PURPOSE: Leptomeningeal metastasis (LM) is an increasingly common complication of late-stage systemic cancer, for which there is no standard treatment. We analyzed outcome and toxicity in patients with LM undergoing craniospinal irradiation via helical tomotherapy (HT-CSI) at our institution. PATIENTS AND METHODS: The charts of 15 patients diagnosed with LM and undergoing HT-CSI between 2006 and 2014 were retrospectively assessed. Main neoplasms included breast cancer, lung cancer, and lymphoma. All patients presented with cranial neuropathy due to LM. Follow-up was performed regularly. Survival analysis was performed by the Kaplan-Meier method, and prognostic factors were tested using the COX-regression model. RESULTS: Median survival by cancer type was 6 (breast cancer), 1 (lung cancer), and 2 months (lymphoma), respectively. Median overall survival and relapse-free survival were calculated to be between 2 and 3 months. Six- and 12-month survival was 30% (95% CI 0.08-0.5) and 20% (95% CI 0.05-0.4), respectively. Symptom palliation occurred in 53% of patients in general, but in 67% of breast cancer patients, in particular. Patients with lung cancer experienced no improvement. Most common acute treatment-related toxicity at different levels were hematological toxicity, multiple cranial neuropathy, fatigue, infections, nausea, and headache. CONCLUSION: HT-CSI can help meet the challenge of treating patients with LM, especially because it can palliate symptoms and improve neurological functions. One-year survival remains as disappointing as before.

PSMA-PET based radiotherapy: a review of initial experiences, survey on current practice and future perspectives.

68Gallium prostate specific membrane antigen (PSMA) ligand positron emission tomography (PET) is an increasingly used imaging modality in prostate cancer, especially in cases of tumor recurrence after curative intended therapy. Owed to the novelty of the PSMA-targeting tracers, clinical evidence on the value of PSMA-PET is moderate but rapidly increasing. State of the art imaging is pivotal for radiotherapy treatment planning as it may affect dose prescription, target delineation and use of concomitant therapy.This review summarizes the evidence on PSMA-PET imaging from a radiation oncologist's point of view. Additionally a short survey containing twelve examples of patients and 6 additional questions was performed in seven mayor academic centers with experience in PSMA ligand imaging and the findings are reported here.

Dosimetric quantification of the incidental irradiation of the 'true' (deep) ano-inguinal lymphatic drainage of anal cancer patients not described in conventional contouring guidelines.

INTRODUCTION: The ano-inguinal lymphatic drainage (AILD) is located in the subcutaneous adipose tissue of the proximal medial thigh. Findings from fluorescence methods give us new information about anatomical conditions of the AILD. Current contouring guidelines do not advise the inclusion of the 'true' AILD into the clinical target volume (CTV). Aim of this work was the retrospective analysis of the incidental dose to the AILD in an anal cancer (AC) patient cohort who underwent definitive chemoradiation (CRT) therapy with Volumetric Arc Therapy - Intensity Modulated Radiation Therapy (VMAT-IMRT). METHODS: VMAT-IMRT plans of 15 AC patients were analyzed. Based on findings from new fluorescence methods we created a new volume, the expected AILD. The examined dosimetric parameters were the minimal, maximal and mean dose and V10-V50 that were delivered to the AILD, respectively. RESULTS: The median volume of AILD was 1047 cm³. Mean Dmin, Dmax and Dmean were 7.5 Gy, 58.9 Gy and 40.8 Gy for AILD. The clinical relevant dose of 30.0 Gray covered in mean 76% of the volume of the AILD, respectively. CONCLUSIONS: Only 76% of the AILD-volume received at least an expected required treatment dose of 30 Gy incidentally. Concerning the low number of loco-regional relapses in AC patients after definitive CRT one has to balance increased side effects against a rigid oncological-anatomical interpretation of the local lymphatic drainage by including the AILD into the standard CTV.

Oligometastases from prostate cancer: local treatment with stereotactic body radiotherapy (SBRT).

BACKGROUND: The impact of local tumor ablative therapy in oligometastasized prostate cancer (PC) is still under debate. To gain data for this approach, we evaluated oligometastasized PC patients receiving stereotactic body radiotherapy (SBRT) to bone metastases. METHODS: In this retrospective study, 15 oligometastasized PC patients with a total of 20 bone metastases were evaluated regarding biochemical progression-free survival (PSA-PFS), time to initiation of ADT, and local control rate (LCR). Three patients received concomitant androgen deprivation therapy (ADT). RESULTS: The median follow-up after RT was 22.5 months (range 7.0-53.7 months). The median PSA-PFS was 6.9 months (range 1.1-28.4 months). All patients showing a decrease of PSA level after RT of at least factor 10 reveal a PSA-PFS of >12 months. Median PSA-PFS of this sub-group was 23.1 months (range 12.1-28.4 months). Local PFS (LPFS) after 2 years was 100%. One patient developed a local failure after 28.4 months. Median distant PFS (DPFS) was 7.36 months (range 1.74-54.34 months). The time to initiation of ADT in patients treated without ADT was 9.3 months (range 2.6-36.1 months). In all patients, the time to intensification of systemic therapy or the time to initiation of ADT increased from 9.3 to 12.3 months (range 2.6-36.1 months). Gleason-Score, ADT or the localization of metastasis had no impact on PFS or time to intensification of systemic therapy. No SBRT related acute or late toxicities were observed. CONCLUSION: Our study shows that SBRT of bone metastases is a highly effective therapy with an excellent risk-benefit profile. However, PFS was limited due to a high distant failure rate implying the difficulty for patient selection for this oligometastatic concept. SBRT offers high local cancer control rates in bone oligometastases of PC and should be evaluated with the aim of curation or to delay modification of systemic treatment.

68 Ga-PSMA-PET for radiation treatment planning in prostate cancer recurrences after surgery: Individualized medicine or new standard in salvage treatment.

BACKGROUND: 68 Ga-PSMA-PET imaging is a novel promising diagnostic tool to locate early biochemical failure after radical prostatectomy (RP) in prostate cancer (PC) patients. Exact knowledge of the relapse location may result in changes of the therapy concept aside from changes to the TNM stage. To gain data for this approach, we evaluated PC patients receiving 68 Ga-PSMA-PET imaging before salvage radiotherapy (RT). METHODS AND MATERIALS: In this study, 100 patients with biochemical failure after RP± prior RT who underwent 68 Ga-PSMA PET/CT or PET/MRI were evaluated undergoing salvage RT in our department. We analyzed TNM staging changes due to 68 Ga-PSMA-PET imaging and its influence on RT planning and treatment. RESULTS: Uptake indicative for tumor recurrence in 68 Ga-PSMA-PET was found in 76% of the patients with biochemical recurrent PC. Median PSA level was 1.0 ng/mL (range 0.12-14.7 ng/mL). Of these, 80% showed no morphological correlate in the corresponding CT or MRI. A 43% of all patients experienced a change in TNM stage due to 68 Ga-PSMA-PET imaging. Patients had changes from Tx to rcT+ (28%), 12% from pN0 to rcN1, 1% from pN0/cM0 to rcM1a, and 8% from cM0 to rcM1b. Due to the additional knowledge of 68 Ga-PSMA-PET imaging, initial planned RT planning was adapted in 59% of all cases. An additional simultaneous integrated boost (SIB) to the prostate bed or lymph nodes was given to 32% and 63%, respectively. Ten patients received stereotactic body RT (SBRT) to single bone metastases. CONCLUSION: 68 Ga-PSMA-PET imaging showed a high clinical impact on staging and RT management in patients with biochemically recurrent PC, even at low serum PSA levels. With 43% changes in staging and 59% in radiotherapy planning 68 Ga-PSMA-PET could lead to an indispensable tool in guiding radiation treatment in recurrent PC.

Detection Efficacy of Hybrid 68Ga-PSMA Ligand PET/CT in Prostate Cancer Patients with Biochemical Recurrence After Primary Radiation Therapy Defined by Phoenix Criteria.

The aim of this retrospective study was to evaluate the detection rate of Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)] (68Ga-PSMA ligand; PSMA is prostate-specific membrane antigen) PET/CT in patients with biochemical recurrent prostate cancer defined by Phoenix criteria after external-beam radiotherapy or brachytherapy as primary treatment. Methods: One hundred eighteen patients with a median prostate-specific antigen (PSA) of 6.4 ng/mL (range, 2.2-158.4 ng/mL; interquartile range, 4.2-10.2 ng/mL) were finally eligible for this retrospective analysis. Seventy-seven and 41 patients had been treated by external-beam radiotherapy or brachytherapy, respectively. Of the 118 patients, 45 were receiving androgen-deprivation therapy (ADT) within at least 6 mo before the PET/CT. The detection rates were stratified by PSA. The influence of primary Gleason score and ADT was assessed. Relationships between SUV and clinical as well as pathologic features in patients with positive findings were analyzed using univariate and multivariable linear regression models. Results: One hundred seven of 118 patients (90.7%) showed pathologic findings indicative for tumor recurrence in 68Ga-PSMA ligand PET/CT. The detection rates were 81.8% (36/44), 95.3% (41/43), and 96.8% (30/31) for PSA of 2 to <5, 5 to <10, and ≥10 ng/mL, respectively (P = 0.0377). 68Ga-PSMA ligand PET/CT indicated local recurrence in 68 of 107 patients (63.5%), distant lesions in 64 of 107 patients (59.8%), and local recurrence as well as distant lesions in 25 of 107 patients (23.4%). The detection rate was significantly higher in patients with ADT (97.7%) versus without ADT (86.3%, P = 0.0381), but independent from primary Gleason score ≥ 8 (92.0%) versus ≤ 7 (90.2%, P = 0.6346). SUVmax and SUVmean were significantly associated with PSA and ADT (P = 0.018 and 0.004 for SUVmax, respectively; P = 0.025 and 0.007 for SUVmean, respectively). Conclusion:68Ga-PSMA ligand PET/CT demonstrates high detection rates in patients with biochemical recurrence of prostate cancer after primary radiation therapy. The detection rate was positively associated to increasing PSA as well as concomitant ADT. 68Ga-PSMA ligand PET/CT enables discrimination of local versus metastatic disease and thus might have a crucial impact on further clinical management. A major limitation of this study is the lack of histopathologic proof in most patients.

Craniospinal irradiation using helical tomotherapy for central nervous system tumors.

The aim of this study was to describe early and late toxicity, survival and local control in 45 patients with primary brain tumors treated with helical tomotherapy craniospinal irradiation (HT-CSI). From 2006 to 2014, 45 patients with central nervous system malignancies were treated with HT-CSI. The most common tumors were medulloblastoma in 20 patients, ependymoma in 10 patients, intracranial germinoma (ICG) in 7 patients, and primitive neuroectodermal tumor in 4 patients. Hematological toxicity during treatment included leukopenia Grades 1-4 (6.7%, 33.3%, 37.8% and 17.8%, respectively), anemia Grades 1-4 (44.4%, 22.2%, 22.2% and 0%, respectively) and thrombocytopenia Grades 1-4 (51.1%, 15.6%, 15.6% and 6.7%, respectively). The most common acute toxicities were nausea, vomiting, fatigue, loss of appetite, alopecia and neurotoxicity. No Grade 3 or higher late toxicity occurred. The overall 3- and 5-year survival rates were 80% and 70%, respectively. Survival for the main tumor entities included 3- and 5-year survival rates of 80% and 70%, respectively, for patients with medulloblastoma, 70% for both in patients with ependymoma, and 100% for both in patients with ICG. Relapse occurred in 11 patients (24.4%): 10 with local and 1 with multifocal relapse. One patient experienced a secondary cancer. M-status and the results of the re-evaluation at the end of treatment were significantly related to survival. Survival after HT-CSI was in line with the existing literature, and acute treatment-induced toxicity resolved quickly. Compared with conventional radiotherapy, HT offers benefits such as avoiding gaps and junctions, sparing organs, and better and more homogeneous dose distribution and coverage of the target volume.

Interdisciplinary consensus statement on indication and application of a hydrogel spacer for prostate radiotherapy based on experience in more than 250 patients.

BACKGROUND: The aim of the study was to reach a consensus on indication and application of a hydrogel spacer based on multicentre experience and give new users important information to shorten the learning curve for this innovative technique. METHODS: The interdisciplinary meeting was attended by radiation oncologists and urologists, each with experience of 23 - 138 hydrogel injections (SpaceOAR®) in prostate cancer patients before dose-escalated radiotherapy. User experience was discussed and questions were defined to comprise practical information relevant for successful hydrogel injection and treatment. Answers to the defined key questions were generated. Hydrogel-associated side effects were collected to estimate the percentage, treatment and prognosis of potential risks. RESULTS: The main indication for hydrogel application was dose-escalated radiotherapy for histologically confirmed low or intermediate risk prostate cancer. It was not recommended in locally advanced prostate cancer. The injection or implantation was performed under transrectal ultrasound guidance via the transperineal approach after prior hydrodissection. The rate of injection-related G2-toxicity was 2% (n = 5) in a total of 258 hydrogel applications. The most frequent complication (n = 4) was rectal wall penetration, diagnosed at different intervals after hydrogel injection and treated conservatively. CONCLUSIONS: A consensus was reached on the application of a hydrogel spacer. Current experience demonstrated feasibility, which could promote initiation of this method in more centres to reduce radiation-related gastrointestinal toxicity of dose-escalated IGRT. However, a very low rate of a potential serious adverse event could not be excluded. Therefore, the application should carefully be discussed with the patient and be balanced against potential benefits.

Integration of (68)Ga-PSMA-PET imaging in planning of primary definitive radiotherapy in prostate cancer: a retrospective study.

BACKGROUND: Prostate cancer (PC) is one of the most commonly treated cancer entities with radiation therapy (RT). Risk group-adapted treatment and avoidance of unnecessary toxicities relies primarily on accurate tumor staging. Thus, the introduction of prostate-specific membrane antigen (PSMA) in diagnosis and treatment of PC is a highly interesting development in radiation oncology of urologic tumors. The present work is to evaluate the integration of (68)Ga-PSMA-PET imaging into standard radiation planning of primary definitive treatment of PC and to determine the impact of PSMA imaging on tumor staging. METHODS: The data of 15 patients treated for PC between August 2013 and April 2015 were evaluated. Treatment planning included (68)Ga-PSMA-PET imaging. We analyzed whether the use of PSMA-imaging led to a change of the TNM stage and if it influenced the RT treatment approach or the target volume, due to changes in the gross tumor volume (GTV) or clinical target volume (CTV), in the final treatment plan. RESULTS: In 53.3 % of the analyzed patients a change occurred in the TNM stage based on (68)Ga-PSMA-PET examination. The RT concept changed in 33.3 % of all patients, leading to relevant changes in the planning target volume. Among these, an additional irradiation of the pelvic lymph drainage due to tracer uptake in lymph nodes was performed in 25 %. Furthermore, boost volumes of PET-positive lymph nodes were added in 80 % of these cases. A down staging due to the (68)Ga-PSMA-PET examination occurred in 13.3 % of all cases. CONCLUSIONS: The integration of (68)Ga-PSMA-PET-imaging into the RT treatment planning process can be useful for detailed target volume planning. The performance of a (68)Ga-PSMA-PET frequently leads to changes in the TNM stage, altering the RT treatment regimen and the target volume. A prospective trial is underway to evaluate the impact of (68)Ga-PSMA-PET based treatment planning on outcome.

Rationale of hyperthermia for radio(chemo)therapy and immune responses in patients with bladder cancer: Biological concepts, clinical data, interdisciplinary treatment decisions and biological tumour imaging.

Bladder cancer, the most common tumour of the urinary tract, ranks fifth among all tumour entities. While local treatment or intravesical instillation of bacillus Calmette-Guerin (BCG) provides a treatment option for non-muscle invasive bladder cancer of low grade, surgery or radio(chemo)therapy (RT) are frequently applied in high grade tumours. It remains a matter of debate whether surgery or RT is superior with respect to clinical outcome and quality of life. Surgical resection of bladder cancer can be limited by acute side effects, whereas, RT, which offers a non-invasive treatment option with organ- and functional conservation, can cause long-term side effects. Bladder toxicity by RT mainly depends on the total irradiation dose, fraction size and tumour volume. Therefore, novel approaches are needed to improve clinical outcome. Local tumour hyperthermia is currently used either as an ablation therapy or in combination with RT to enhance anti-tumour effects. In combination with RT an increase of the temperature in the bladder stimulates the local blood flow and as a result can improve the oxygenation state of the tumour, which in turn enhances radiation-induced DNA damage and drug toxicity. Hyperthermia at high temperatures can also directly kill cells, particularly in tumour areas which are poorly perfused, hypoxic or have a low tissue pH. This review summarises current knowledge relating to the role of hyperthermia in RT to treat bladder cancer, the induction and manifestation of immunological responses induced by hyperthermia, and the utilisation of the stress proteins as tumour-specific targets for tumour detection and monitoring of therapeutic outcome.

Acute Toxicity and Quality of Life in Patients With Prostate Cancer Treated With Protons or Carbon Ions in a Prospective Randomized Phase II Study--The IPI Trial.

PURPOSE: The purpose of this study was to compare safety and feasibility of proton therapy with that of carbon ion therapy in hypofractionated raster-scanned irradiation of the prostate, in a prospective randomized phase 2 trial. METHODS AND MATERIALS: In this trial, 92 patients with localized prostate cancer were enrolled. Patients were randomized to receive either proton therapy (arm A) or carbon ion therapy (arm B) and treated with a total dose of 66 Gy(relative biological effectiveness [RBE]) administered in 20 fractions (single dose of 3.3 Gy[RBE]). Patients were stratified by the use of antihormone therapy. Primary endpoint was the combined assessment of safety and feasibility. Secondary endpoints were specific toxicities, prostate-specific antigen progression-free survival (PFS), overall survival (OS), and quality of life (QoL). RESULTS: Ninety-one patients completed therapy and have had a median follow-up of 22.3 months. Among acute genitourinary toxicities, grade 1 cystitis rates were 34.1% (39.1% in A; 28.9% in B) and 17.6% grade 2 (21.7% in A; 13.3% in B). Seven patients (8%) required urinary catheterization during treatment due to urinary retention, 5 of whom were in arm A. Regarding acute gastrointestinal toxicities, 2 patients treated with protons developed grade 3 rectal fistulas. Grade 1 radiation proctitis occurred in 12.1% (13.0% in A; 11.1% in B) and grade 2 in 5.5% (8.7% in A; 2.2% in B). No statistically significant differences in toxicity profiles between arms were found. Reduced QoL was evident mainly in fatigue, pain, and urinary symptoms during therapy and 6 weeks thereafter. All European Organization for Research and Treatment of Cancer QLQ-C30 and -PR25 scores improved during follow-up. CONCLUSIONS: Hypofractionated irradiation using either carbon ions or protons results in comparable acute toxicities and QoL parameters. We found that hypofractionated particle irradiation is feasible and may be safe. Due to the occurrence of gel in the rectal wall and the consecutive occurrence of 2 rectal fistulas, we stopped using the insertion of spacer gel. Longer follow-up is necessary for evaluation of PFS and OS. (Ion Prostate Irradiation (IPI); NCT01641185; ClinicalTrials.gov.).

Protons, Photons, and the Prostate - Is There Emerging Evidence in the Ongoing Discussion on Particle Therapy for the Treatment of Prostate Cancer?

Proton therapy is actively and repeatedly discussed within the framework of particle therapy for the treatment of prostate cancer (PC). The argument in favor of treating the prostate with protons is partly financial: given that small volumes are treated, treatment times are low, resulting in a hypothetical high patient throughput. However, such considerations should not form the basis of medical decision-making. There are also physical and biological arguments which further support the use of particle therapy for PC. The only relevant randomized data currently available is the study by Zietman and colleagues, comparing a high to a low proton boost, resulting in a significant increase in PSA-free survival in the experimental (high dose) arm (1). With modern photon treatments and image-guided radiotherapy (IGRT), equally high doses can be applied with photons and, thus, a randomized trial comparing high-end photons to protons is warranted. For high-linear energy transfer (LET) particles, such as carbon ions, the increase in relative biological effectiveness could potentially convert into an improvement in outcome. Additionally, through the physical differences of protons and carbon ions, the steeper dose gradient with carbon ions and the lack of beam broadening in the carbon beam lead to a superior dose distribution supporting the idea of hypofractionation. Biological and clinical data are emerging, however, has practice-changing evidence already arrived?

Scanned ion beam therapy for prostate carcinoma: Comparison of single plan treatment and daily plan-adapted treatment.

BACKGROUND AND PURPOSE: Intensity-modulated particle therapy (IMPT) for tumors showing interfraction motion is a topic of current research. The purpose of this work is to compare three treatment strategies for IMPT to determine potential advantages and disadvantages of ion prostate cancer therapy. MATERIALS AND METHODS: Simulations for three treatment strategies, conventional one-plan radiotherapy (ConvRT), image-guided radiotherapy (IGRT), and online adaptive radiotherapy (ART) were performed employing a dataset of 10 prostate cancer patients with six CT scans taken at one week intervals. The simulation results, using a geometric margin concept (7-2 mm) as well as patient-specific internal target volume definitions for IMPT were analyzed by target coverage and exposure of critical structures on single fraction dose distributions. RESULTS: All strategies led to clinically acceptable target coverage in patients exhibiting small prostate motion (mean displacement <4 mm), but IGRT and especially ART led to significant sparing of the rectum. In 20% of the patients, prostate motion exceeded 4 mm causing insufficient target coverage for ConvRT (V95mean = 0.86, range 0.63-0.99) and IGRT (V95mean = 0.91, range 0.68-1.00), while ART maintained acceptable target coverage. CONCLUSION: IMPT of prostate cancer demands consideration of rectal sparing and adaptive treatment replanning for patients exhibiting large prostate motion.

(68)Ga-PSMA-11 PET/CT: a new technique with high potential for the radiotherapeutic management of prostate cancer patients.

PURPOSE: Radiotherapy is the main therapeutic approach besides surgery of localized prostate cancer. It relies on risk stratification and exact staging. This report analyses the potential of [(68)Ga]Glu-urea-Lys(Ahx)-HBED-CC ((68)Ga-PSMA-11), a new positron emission tomography (PET) tracer targeting prostate-specific membrane antigen (PSMA) for prostate cancer staging and individualized radiotherapy planning. METHODS: A cohort of 57 patients with prostate cancer scanned with (68)Ga-PSMA-11 PET/CT for radiotherapy planning was retrospectively reviewed; 15 patients were at initial diagnosis and 42 patients at time of biochemical recurrence. Staging results of conventional imaging, including bone scintigraphy, CT or MRI, were compared with (68)Ga-PSMA ligand PET/CT results and the influence on radiotherapeutic management was quantified. RESULTS: (68)Ga-PSMA ligand PET/CT had a dramatic impact on radiotherapy application in the presented cohort. In 50.8 % of the cases therapy was changed. CONCLUSION: The presented imaging technique of (68)Ga-PSMA PET/CT could be a key technology for individualized radiotherapy management in prostate cancer.

Helical intensity-modulated radiotherapy of the pelvic lymph nodes with a simultaneous integrated boost to the prostate--first results of the PLATIN 1 trial.

BACKGROUND: Definitive, percutaneous irradiation of the prostate and the pelvic lymph nodes in high-risk prostate cancer is the alternative to prostatectomy plus lymphadenectomy. To date, the role of whole pelvis radiotherapy (WPRT) has not been clarified especially taking into consideration the benefits of high conformal IMRT (intensity modulated radiotherapy) of complex-shaped target volumes. METHODS: From 2009 to 2012, 40 patients of high-risk prostate cancer with an increased risk of microscopic lymph node involvement were enrolled into this prospective phase II trial. Patients received at least two months of antihormonal treatment (AT) before radiotherapy continuing for at least 2 years. Helical IMRT (tomotherapy) of the pelvic lymph nodes (51.0 Gy) with a simultaneous integrated, moderate hypofractionated boost (single dose of 2.25 Gy) to the prostate (76.5 Gy) was performed in 34 fractions. PSA levels, prostate-related symptoms and quality of life were assessed at regular intervals for 24 months. RESULTS: Of the 40 patients enrolled, 38 finished the treatment as planned. Overall acute toxicity rates were low and no acute grade 3 or 4 gastrointestinal (GI) and genitourinary (GU) toxicity occurred. 21.6% of patients experienced acute grade 2 but no late grade ≥ 2 GI toxicity. Regarding GU side effects, results showed 48.6% acute grade 2 and 6.4% late grade 2 toxicity. After a median observation time of 23.4 months the PLATIN 1 trial can be considered as sufficiently safe meeting the prospectively defined aims of the trial. With 34/37 patients free of a PSA recurrence it shows promising efficacy. CONCLUSION: Tomotherapy of the pelvic lymph nodes with a simultaneous integrated boost to the prostate can be performed safely and without excessive toxicity. The combined irradiation of both prostate and pelvic lymph nodes seems to be as well tolerated as the irradiation of the prostate alone. TRIAL REGISTRATION: Trial Numbers: ARO 2009-05, ClinicalTrials.gov: NCT01903408.

Heat Shock Protein 70 (Hsp70) Peptide Activated Natural Killer (NK) Cells for the Treatment of Patients with Non-Small Cell Lung Cancer (NSCLC) after Radiochemotherapy (RCTx) - From Preclinical Studies to a Clinical Phase II Trial.

Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both study groups.