Barbara Alicja Jereczek-Fossa

Radiotherapy-related fatigue.

Radiotherapy-induced fatigue is a common early and chronic side-effect of irradiation, reported in up to 80 and 30% of patients during radiation therapy and at follow-up visits, respectively. It is frequently underestimated by medical and nursing staff, only about 50% of patients discuss it with a physician and in one fourth of cases any intervention is proposed to the patient. The patients rarely expect fatigue to be a side-effect of treatment. The etiology of this common symptom, its correlates and prevalence are poorly understood. In numerous studies the level and time course of fatigue was demonstrated to depend on the site of tumor and treatment modalities. For example, psychological mechanisms have been proposed to explain fatigue in women receiving irradiation for early breast cancer, whereas decline in neuromuscular efficiency rather than psychological reasons can lead to the fatigue observed in patients undergoing radiotherapy for prostate cancer. Fatigue can affect global quality of life more than pain, sexual dysfunction and other cancer- or treatment-related symptoms. Several interventions have been tested in the management of radiotherapy-related fatigue and some randomized studies have been recently published. Although an optimal method has not yet been established, some promising results have been reported with relaxation therapy, group psychotherapy, physical exercise and sleep. Further methodologically correct studies are warranted to define better the causes, optimal prevention and management of this symptom.

Robotic Image-Guided Stereotactic Radiotherapy, for Isolated Recurrent Primary, Lymph Node or Metastatic Prostate Cancer

PURPOSE To evaluate the outcome of robotic CyberKnife (Accuray, Sunnyvale, CA)-based stereotactic radiotherapy (CBK-SRT) for isolated recurrent primary, lymph node, or metastatic prostate cancer. METHODS AND MATERIALS Between May 2007 and December 2009, 34 consecutive patients/38 lesions were treated (15 patients reirradiated for local recurrence [P], 4 patients reirradiated for anastomosis recurrence [A], 16 patients treated for single lymph node recurrence [LN], and 3 patients treated for single metastasis [M]). In all but 4 patients, [(11)C]choline positron emission tomography/computed tomography was performed. CBK-SRT consisted of reirradiation and first radiotherapy in 27 and 11 lesions, respectively. The median CBK-SRT dose was 30 Gy in 4.5 fractions (P, 30 Gy in 5 fractions; A, 30 Gy in 5 fractions; LN, 33 Gy in 3 fractions; and M, 36 Gy in 3 fractions). In 18 patients (21 lesions) androgen deprivation was added to CBK-SRT (median duration, 16.6 months). RESULTS The median follow-up was 16.9 months. Acute toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event). Late toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event and 1 Grade 2 event). Biochemical response was observed in 32 of 38 evaluable lesions. Prostate-specific antigen stabilization was seen for 4 lesions, and in 2 cases prostate-specific antigen progression was reported. The 30-month progression-free survival rate was 42.6%. Disease progression was observed for 14 lesions (5, 2, 5, and 2 in Groups P, A, LN, and M respectively). In only 3 cases, in-field progression was seen. At the time of analysis (May 2010), 19 patients are alive with no evidence of disease and 15 are alive with disease. CONCLUSIONS CyberKnife-based stereotactic radiotherapy is a feasible approach for isolated recurrent primary, lymph node, or metastatic prostate cancer, offering excellent in-field tumor control and a low toxicity profile. Further investigation is warranted to identify the patients who benefit most from this treatment modality. The optimal combination with androgen deprivation should also be defined.

Radiotherapy-induced ear toxicity

Despite their particular functional consequences, radiotherapy-induced ear injuries remain under-evaluated and under-reported. These reactions may have acute or late character, may affect all structures of the hearing organ, and result in conductive, sensorineural or mixed hearing loss. Up to 40% of patients have acute middle ear side effects during radical irradiation including acoustic structures and about one-third of patients develop late sensorineural hearing loss (SNHL). Total radiotherapy dose and tumour site seem to be among the most important factors associated with the risk of hearing impairment. Thus, reduction in radiation dose to the auditory structures should be attempted whenever possible. New radiotherapy techniques (3-dimensional conformal irradiation, intensity modulated radiotherapy, proton therapy) allow better dose distribution with lower dose to the non-target organs. Treatment of acute and late external otitis is mainly conservative and includes the anti-inflammatory agents (applied topically and systematically). Post-radiation chronic otitis media and the eustachian tube pathology may be managed with tympanic membrane incision with insertion of a tympanostomy tube (grommet), although the benefit of such approach is controversial and some authors advocate a more conservative approach. In these patients the functional deficit can be alleviated by application of bone conduction hearing aids such as, e.g., the bone anchored hearing aid (BAHA). There is no standard therapy for post-irradiation sudden or progressive SNHL yet corticosteroid therapy, rheologic medications, hyperbaric oxygen or carbogen therapy are usually employed (as for idiopathic SNHL), although controversial data on the efficacy of these treatment modalities have been published. In selected cases with bilateral profound hearing loss or total deafness, cochlear implants may prove effective. Further improvements in radiotherapy techniques and progress in otologic diagnostics and therapy may allow better prevention and management of radiation-related acoustic injury.

Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis

UNLABELLED The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) recurrence consists of small heterogeneous studies. This study aimed to reduce the heterogeneity by pooling individual patient data from different institutions treating oligometastatic PCa recurrence with stereotactic body radiotherapy (SBRT). We focussed on patients who were treatment naive, with the aim of determining if SBRT could delay disease progression. We included patients with three or fewer metastases. The Kaplan-Meier method was used to estimate distant progression-free survival (DPFS) and local progression-free survival (LPFS). Toxicity was scored using the Common Terminology Criteria for Adverse Events. In total, 163 metastases were treated in 119 patients. The median DPFS was 21 mo (95% confidence interval, 15-26 mo). A lower radiotherapy dose predicted a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with a biologically effective dose ≤100Gy versus 99% for patients treated with >100Gy (p=0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three patients (3%) developed grade 2 toxicity. No grade ≥3 toxicity occurred. These results should serve as a benchmark for future prospective trials. PATIENT SUMMARY This multi-institutional study pools all of the available data on the use of stereotactic body radiotherapy for limited prostate cancer metastases. We concluded that this approach is safe and associated with a prolonged treatment progression-free survival.

RECURRENT ENDOMETRIAL CANCER AFTER SURGERY ALONE: RESULTS OF SALVAGE RADIOTHERAPY

PURPOSE Postoperative irradiation of endometrial cancer patients decreases the risk of local recurrence but is associated with a number of long-term sequelae. In a proportion of patients, no immediate postoperative radiotherapy is applied and this treatment is introduced only at relapse. The aim of our study was to assess the long-term results of salvage radiotherapy in previously nonirradiated endometrial cancer patients who developed local recurrence, and to evaluate the impact of patient- and treatment-related factors on treatment efficacy. METHODS AND MATERIALS We performed a detailed retrospective analysis of 73 endometrial cancer patients given radiotherapy for local recurrence after the initial surgery only. The mean age at diagnosis of the recurrence was 63 years (range, 39-78 years). Median time to recurrence was 11 months (range, 1-19 months). All recurrences were staged with the use of Perez modification of the International Federation of Gynecology and Obstetrics (FIGO) staging system for primary vaginal carcinoma. There were five (7%) Stage I patients, 43 (59%) Stage II patients, and 25 (34%) Stage III patients. Forty-four patients (60%) received both external beam irradiation (EBRT) and endovaginal brachytherapy (BRT), 17 (23%) received only BRT, and 12 (17%) received only EBRT. The mean total physical radiation dose was 75.9 Gy (range, 8-130 Gy), and the mean normalized total dose (NTD) calculated on the base of the linear-quadratic model was 86.6 Gy (range, 8.5-171.9 Gy). Median follow-up for alive patients was 8.8 years (range, 3-21 years). The impact of patient-, tumor-, and therapy-related factors on the treatment outcome was evaluated with the use of uni- and multivariate analyses. RESULTS Three- and 5-year overall survival rates were 33% and 25%, respectively. In the univariate analysis, lower stage of recurrent disease (p < 0.0005), combined EBRT and BRT (p = 0.027), higher total radiation dose (p = 0.031), and higher NTD (p = 0.006) were significantly correlated with better survival. In the multivariate analysis, only stage of recurrent disease (p < 0.005) and high total dose (p = 0.047) were independently correlated with better survival. Lower FIGO stage of recurrence (p = 0.023) and higher total dose (p = 0.005) were also independently correlated with longer time to progression, whereas higher radiotherapy dose was the only factor correlated with better local control (p = 0.029). CONCLUSIONS The efficacy of salvage radiotherapy in endometrial cancer patients with local failure after previous surgery is limited. Factors determining treatment outcome include advancement of the tumor at relapse and radiotherapy dose.

PARTICLE BEAM RADIOTHERAPY FOR HEAD AND NECK TUMORS: RADIOBIOLOGICAL BASIS AND CLINICAL EXPERIENCE

Head and neck tumors are often located near critical organs, making it impossible to deliver a dose of conventional radiotherapy high enough to eradicate the disease. Our aim was to review the potential benefits and available clinical experience of particle beam therapy (hadrontherapy) in the treatment of these tumors.

Transabdominal Ultrasonography, Computed Tomography and Electronic Portal Imaging for 3-Dimensional Conformal Radiotherapy for Prostate Cancer

Purpose:To evaluate the feasibility and accuracy of daily B-mode acquisition and targeting ultrasound-based prostate localization (BAT™) and to compare it with computed tomography (CT) and electronic portal imaging (EPI) in 3-dimensional conformal radiotherapy (3-D CRT) for prostate cancer.Patients and Methods:Ten patients were treated with 3-D CRT (72 Gy/30 fractions, 2.4 Gy/fraction, equivalent to 80 Gy/40 fractions, for α/β ratio of 1.5 Gy) and daily BAT-based prostate localization. For the first 5 fractions, CT and EPI were also performed in order to compare organ-motion and set-up error, respectively.Results:287 BAT-, 50 CT- and 46 EPI-alignments were performed. The average BAT-determined misalignments in latero-lateral, antero-posterior and cranio-caudal directions were –0.9 mm ± 3.3 mm, 1.0 mm ± 4.0 mm and –0.9 mm ± 3.8 mm, respectively. The differences between BAT- and CT-determined organ-motion in latero-lateral, antero-posterior and cranio-caudal directions were 2.7 mm ± 1.9 mm, 3.9 ± 2.8 mm and 3.4 ± 3.0 mm, respectively. Weak correlation was found between BAT- and CT-determined misalignments in antero-posterior direction, while no correlation was observed in latero-lateral and cranio-caudal directions. The correlation was more significant when only data of good image-quality patients were analyzed (8 patients).Conclusion:BAT ensures the relative positions of target are the same during treatment and in treatment plan, however, the reliability of alignment is patient-dependent. The average BAT-determined misalignments were small, confirming the prevalence of random errors in 3-D CRT. Further study is warranted in order to establish the clinical value of BAT.Ziel:Ziel dieser Studie ist es, die Möglichkeit und Genauigkeit der täglichen B-mode-Akquisition und zielgerichteten ultraschallbasierten Prostatapositionierung (BAT™) einzuschätzen und sie mit der Computertomographie (CT) und dem elektronischen Portal-Imaging (EPI) bei der 3D-konformalen Strahlentherapie (3D-CRT) des Prostatakrebses zu vergleichen.Patienten und Methodik:10 Patienten wurden mit 3D-CRT (72 Gy/30 Fraktionen, 2,4 Gy/Fraktion, äquivalent zu 80 Gy/40 Fraktionen, α/β-Verhältnis von 1,5 Gy ) und täglicher BAT behandelt. Für die ersten 5 Fraktionen wurden auch CT und EPI durchgeführt, um jeweils die Bewegung der Organe und die Set-up-Fehler zu vergleichen.Ergebnisse:287 BAT-, 50 CT- und 46 EPI-Positionierungen wurden durchgeführt. Der durchschnittliche BAT-Positionierungsfehler war jeweils –0,9 mm ± 3,3 mm, 1,0 mm ± 4,0 mm und –0,9 mm ± 3,8 mm in den latero-lateralen, anterior-posterioren und kraniokaudalen Richtungen. Die Unterschiede zwischen der BAT- und CT-Technik bei der Bestimmung der Organbewegung in den latero-lateralen, anterior-posterioren und kraniokaudalen Richtungen waren jeweils 2,7 mm ± 1,9 mm, 3,9 ± 2,8 mm und 3,4 ± 3,0 mm. Eine sehr geringe Korrelation zwischen BAT- und CT-Positionierungsungenauigkeit wurde nur für die anterior-posteriore Richtung gefunden (R = 0,29, p = 0,04). Die Korrelation war leicht besser, wenn nur die Patienten mit guter Bildqualität analysiert wurden (8 Patienten).Schlussfolgerung:BAT garantiert, dass die relative Position des Ziels dieselbe während der Behandlung und in dem Behandlungsplan ist, obwohl die Genauigkeit der Positionierung patientenabhängig ist. Die durchschnittlichen, mit BAT bestimmten, Positionierungsfehler waren klein und bestätigen, dass der statistische Fehler in 3D-CRT vorwiegend ist. Weitere Studien sind erforderlich, um den klinischen Wert von BAT festzustellen.

Sooner or Later? Outcome Analysis of 431 Prostate Cancer Patients Treated With Postoperative or Salvage Radiotherapy

PURPOSE To evaluate the outcome of postoperative radiotherapy (PORT) and salvage RT (SART) using a three-dimensional conformal two-dynamic arc (3D-ART) or 3D six-field technique in 431 prostate cancer patients. METHODS AND MATERIALS Of the 431 patients, 258 underwent PORT (started <6 months after radical prostatectomy) and 173 underwent SART because of biochemical failure after radical prostatectomy. The median patient age, preoperative prostate-specific antigen level, and Gleason score was 66 years, 9.4 ng/mL, and 7, respectively. The median radiation dose was 70 Gy in 35 fractions for both PORT and SART. The 3D six-field and 3D-ART techniques were used in 25.1% and 74.9% of patients, respectively. Biochemical failure was defined as a post-RT prostate-specific antigen nadir plus 0.1 ng/mL. RESULTS Acute toxicity included rectal events (PORT, 44.2% and 0.8% Grade 1-2 and Grade 3, respectively; SART, 42.2% and 1.2% Grade 1-2 and Grade 3, respectively) and urinary events (PORT, 51.2% and 2.3% Grade 1-2 and Grade 3-4, respectively; SART, 37.6% and 0% Grade 1-2 and Grade 3, respectively). Late toxicity also included rectal events (PORT, 14.7% and 0.8% Grade 1-2 and Grade 3-4, respectively; SART, 15.0% and 0.6% Grade 1-2 and Grade 3, respectively) and urinary events (PORT, 28.3% and 3.7% Grade 1-2 and Grade 3-4, respectively; SART, 19.3% and 0.6% Grade 1-2 and Grade 3, respectively). After a median follow-up of 48 months, failure-free survival, including biochemical and clinical failure, was significantly longer in the PORT patients (79.8% vs. 60.5%, p < 0.0001). Multivariate analysis showed that a prostate-specific antigen level postoperatively but before RT of >/=0.2 ng/mL (p < 0.001), Gleason score >6 (p = 0.025) and use of preoperative androgen deprivation (p = 0.002) correlated significantly with shorter failure-free survival. Multivariate analysis showed that PORT and the 3D-ART technique correlated with greater late urinary toxicity. CONCLUSION PORT and early referral for SART offer better disease control after radical prostatectomy. The greater urinary toxicity occurring after PORT and 3D-ART requires further investigation to improve the therapeutic index.

Relationship between acute and late normal tissue injury after postoperative radiotherapy in endometrial cancer

PURPOSE To evaluate the relationship between acute and late normal tissue reactions in 317 consecutive endometrial cancer patients treated with surgery and adjuvant radiotherapy (RT). METHODS The data of 317 patients (staging according to the International Federation of Gynecology and Obstetrics) treated with postoperative RT were analyzed. Both low-dose-rate brachytherapy and external beam RT were applied in 247 patients (78%); brachytherapy only in 49 (15%) and external beam irradiation only in 21 (7%). The median follow-up was 7.3 years (range 4-21). The European Organization for Research and Treatment of Cancer, Radiation Therapy Oncology Group system with elements of the late effects of normal tissue, subjective, objective, management, analytic (LENT/SOMA) scale was used to score the RT reactions. The correlation between the occurrence and severity of acute and late bowel and bladder toxicity, as well as the relationship between the severity of acute effects and time to occurrence of late reactions, were assessed using linear and logistic regression analyses. RESULTS Of the 317 patients, 268 (85%) experienced acute RT reactions of any grade. Severe acute bowel reactions were observed in 15 patients (5%), urinary bladder complications in 1 patient (0.5%), cutaneous in 1 patient (0.5%), and vaginal in 1 patient (0.5%). Severe acute hematologic toxicity was seen in 3 patients (1%). A total of 158 patients (51%) experienced late RT reactions of any grade. Severe late bowel reactions were observed in 19 patients (6%), urinary bladder in 5 (2%), vaginal in 3 (1%), and bone in 10 (4%). When all toxic events were considered, there was a highly significant correlation between the acute and late bowel reactions (p <0.001), but the acute and late urinary bladder reactions did not correlate (p = 0.64). The grade of acute toxicity was found to predict the grade of late toxicity for the bowel but not for the bladder (p <0.001 and p = 0.47, respectively). The severity of acute bowel and bladder toxicity did not correlate with the time to occurrence of late toxicity in these locations (p = 0.34 and p = 0.47, respectively). CONCLUSION Patients with increased acute bowel toxicity during postoperative RT for endometrial cancer have an increased risk of late bowel injury. A higher grade of acute bowel complications correlated with more severe late events, but was not predictive for its latency time. These findings suggest the possibility of an early indication of patients with an increased risk of late toxicity in whom preventive measures might be attempted.

CORRELATION BETWEEN ACUTE AND LATE TOXICITY IN 973 PROSTATE CANCER PATIENTS TREATED WITH THREE-DIMENSIONAL CONFORMAL EXTERNAL BEAM RADIOTHERAPY

PURPOSE To analyze the correlation between acute and late injury in 973 prostate cancer patients treated with radiotherapy and to evaluate the effect of patient-, tumor-, and treatment-related variables on toxicity. METHODS AND MATERIALS Of the 973 patients, 542 and 431 received definitive or postprostatectomy radiotherapy, respectively. Three-dimensional conformal radiotherapy included a six-field technique and two-dynamic arc therapy. Toxicity was classified according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. The correlation between acute and late toxicity (incidence and severity) was assessed. RESULTS Multivariate analysis showed that age </=65 years (p = .06) and use of the three-dimensional, six-field technique (p <.0001) correlated significantly with greater acute rectal toxicity. The three-dimensional, six-field technique (p = .0002), dose >70 Gy (p = .014), and radiotherapy duration (p = .05) correlated with greater acute urinary toxicity. Acute rectal toxicity (p <.0001) was the only factor that correlated with late rectal injury on multivariate analysis. Late urinary toxicity correlated with acute urinary events (p <.0001) and was inversely related to the use of salvage radiotherapy (p = .018). A highly significant correlation was found between the incidence of acute and late events for both rectal (p <.001) and urinary (p <.001) reactions. The severity of acute toxicity (Grade 2 or greater) was predictive for the severity of late toxicity for both rectal and urinary events (p <.001). CONCLUSION The results of our study have shown that the risk of acute reactions depends on both patient-related (age) and treatment-related (dose, technique) factors. Acute toxicity was an independent significant predictor of late toxicity. These findings might help to predict and prevent late radiotherapy-induced complications.