Kristina Nilsson

Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy.

PURPOSE The impact of stereotactic body radiotherapy (SBRT) on 3-year progression-free survival of medically inoperable patients with stage I non-small-cell lung cancer (NSCLC) was analyzed in a prospective phase II study. PATIENTS AND METHODS Fifty-seven patients with T1NOMO (70%) and T2N0M0 (30%) were included between August 2003 and September 2005 at seven different centers in Sweden, Norway, and Denmark and observed up to 36 months. SBRT was delivered with 15 Gy times three at the 67% isodose of the planning target volume. RESULTS Progression-free survival at 3 years was 52%. Overall- and cancer-specific survival at 1, 2, and 3 years was 86%, 65%, 60%, and 93%, 88%, 88%, respectively. There was no statistically significant difference in survival between patients with T1 or T2 tumors. At a median follow-up of 35 months (range, 4 to 47 months), 27 patients (47%) were deceased, seven as a result of lung cancer and 20 as a result of concurrent disease. Kaplan-Meier estimated local control at 3 years was 92%. Local relapse was observed in four patients (7%). Regional relapse was observed in three patients (5%). Nine patients (16%) developed distant metastases. The estimated risk of all failure (local, regional, or distant metastases) was increased in patients with T2 (41%) compared with those with T1 (18%) tumors (P = .027). CONCLUSION With a 3-year local tumor control rate higher than 90% with limited toxicity, SBRT emerges as state-of-the-art treatment for medically inoperable stage I NSCLC and may even challenge surgery in operable instances.

Stereotactic body radiotherapy for medically inoperable patients with stage I non-small cell lung cancer – A first report of toxicity related to COPD/CVD in a non-randomized prospective phase II study

BACKGROUND AND AIMS In a retrospective study using stereotactic body radiotherapy (SBRT) in medically inoperable patients with stage I NSCLC we previously reported a local control rate of 88% utilizing a median dose of 15Gyx3. This report records the toxicity encountered in a prospective phase II trial, and its relation to coexisting chronic obstructive pulmonary disease (COPD) and cardio vascular disease (CVD). MATERIAL AND METHODS Sixty patients were entered in the study between August 2003 and September 2005. Fifty-seven patients (T1 65%, T2 35%) with a median age of 75 years (59-87 years) were evaluable. The baseline mean FEV1% was 64% and median Karnofsky index was 80. A total dose of 45Gy was delivered in three fractions at the 67% isodose of the PTV. Clinical, pulmonary and radiological evaluations were made at 6 weeks, 3, 6, 9, 12, 18, and 36 months post-SBRT. Toxicity was graded according to CTC v2.0 and performance status was graded according to the Karnofsky scale. RESULTS At a median follow-up of 23 months, 2 patients had relapsed locally. No grade 4 or 5 toxicity was reported. Grade 3 toxicity was seen in 12 patients (21%). There was no significant decline of FEV1% during follow-up. Low grade pneumonitis developed to the same extent in the CVD 3/17 (18%) and COPD 7/40 (18%) groups. The incidence of fibrosis was 9/17 (53%) and pleural effusions was 8/17 (47%) in the CVD group compared with 13/40 (33%) and 5/40 (13%) in the COPD group. CONCLUSION SBRT for stage I NSCLC patients who are medically inoperable because of COPD and CVD results in a favourable local control rate with a low incidence of grade 3 and no grade 4 or 5 toxicity.

Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC : Satellite-A phase II study from the Swedish Lung Cancer Study Group

BACKGROUND Several attempts to increase the locoregional control in locally advanced lung cancer including concurrent chemotherapy, accelerated fractionation and dose escalation have been made during the last years. As the EGFR directed antibody cetuximab has shown activity concurrent with radiotherapy in squamous cell carcinoma of the head and neck, as well as in stage IV NSCLC combined with chemotherapy, we wanted to investigate radiotherapy with concurrent cetuximab in locally advanced NSCLC, a tumour type often over expressing the EGF-receptor. METHODS Between February 2006 and August 2007 75 patients in stage III NSCLC with good performance status (PS 0 or 1) and adequate lung function (FEV1>1.0) were enrolled in this phase II study at eight institutions. Treatment consisted of 2 cycles of induction chemotherapy, docetaxel 75 mg/m² and cisplatin 75 mg/m² with 3 weeks interval. An initial dose of cetuximab 400 mg/m² was given before start of 3D-CRT to 68 Gy with 2 Gy per fraction in 7 weeks concurrent with weekly cetuximab 250 mg/m². TOXICITY was scored weekly during radiotherapy (CTC 3.0), and after treatment the patients were followed every third month with CT-scans, toxicity scoring and QLQ. RESULTS Seventy-one patients were eligible for analysis as four were incorrectly enrolled. HISTOLOGY adenocarcinoma 49%, squamous cell carcinoma 39% and other NSCLC 12%. The majority had PS 0 (62.5%), median age 62.2 (42-81), 50% were women and 37% had a pre-treatment weight loss>5%. TOXICITY esophagitis grade 1-2: 72%; grade 3: 1.4%. Hypersensitivity reactions grade 3-4: 5.6%. Febrile neutropenia grade 3-4: 15.4%. Skin reactions grade 1-2: 74%; grade 3: 4.2%. Diarrhoea grade 1-2: 38%; grade 3: 11.3%. Pneumonitis grade 1-2: 26.8%; grade 3: 4.2%; grade 5: 1.4%. The median follow-up was 39 months for patients alive and the median survival was 17 months with a 1-, 2- and 3-year OS of 66%, 37% and 29% respectively. Until now local or regional failure has occurred in 20 patients and 22 patients have developed distant metastases. Weight loss, PS and stage were predictive for survival in univariate as well as in multivariate analysis. CONCLUSION Induction chemotherapy followed by concurrent cetuximab and RT to 68 Gy is clearly feasible with promising survival. TOXICITY, e.g. pneumonitis and esophagitis is low compared to most schedules with concurrent chemotherapy. This treatment strategy should be evaluated in a randomised manner vs. concurrent chemoradiotherapy to find out if it is a valid treatment option.

Survival in primary lung cancer potentially cured by operation: influence of tumor stage and clinical characteristics.

BACKGROUND Surgical resection is currently standard treatment in early stage lung cancer. The aim of the present study was to identify stage-related factors and patient characteristics influencing survival after complete resection. METHODS We identified 395 patients with non-small cell lung cancer who had undergone potentially radical operation during 1987 to 1999 at one thoracic surgery institution in central Sweden. Factors independently related to survival were identified in a multivariate analysis. Survival was analyzed in low-, medium-, and high-risk groups based on a risk score calculated from relative hazards for identified risk factors. RESULTS Overall 5-year survival among the 395 patients was 51%. The strongest factor predicting prognosis was positive lymph nodes at operation. Higher age, earlier period for operation, impaired lung function, current smoking, and major operative complication were all related to poorer prognosis. Patients with tumor stage Ia had a 5-year survival of 69%, compared to 73% in patients in the low-risk group. CONCLUSIONS Tumor stage is the best prognostic indicator after radical operation. Inclusion of other tumor- and patient-related variables did not add prognostic information of clinical relevance beyond that provided by tumor stage alone.

NTCP modelling of lung toxicity after SBRT comparing the universal survival curve and the linear quadratic model for fractionation correction

Abstract Background. In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of lung toxicity is found. The aim of this study is to compare the LQ model and the universal survival curve (USC) to calculate biologically equivalent doses in SBRT to see if this will improve knowledge on this relationship. Material and methods. Toxicity data on radiation pneumonitis grade 2 or more (RP2+) from 57 patients were used, 10.5% were diagnosed with RP2+. The lung DVHs were corrected for fractionation (LQ and USC) and analysed with the Lyman- Kutcher-Burman (LKB) model. In the LQ-correction α/β = 3 Gy was used and the USC parameters used were: α/β = 3 Gy, D0 = 1.0 Gy, = 10, α = 0.206 Gy−1 and dT = 5.8 Gy. In order to understand the relative contribution of different dose levels to the calculated NTCP the concept of fractional NTCP was used. This might give an insight to the questions of whether “high doses to small volumes” or “low doses to large volumes” are most important for lung toxicity. Results and Discussion. NTCP analysis with the LKB-model using parameters m = 0.4, D50 = 30 Gy resulted for the volume dependence parameter (n) with LQ correction n = 0.87 and with USC correction n = 0.71. Using parameters m = 0.3, D50 = 20 Gy n = 0.93 with LQ correction and n = 0.83 with USC correction. In SBRT of lung tumours, NTCP modelling of lung toxicity comparing models (LQ,USC) for fractionation correction, shows that low dose contribute less and high dose more to the NTCP when using the USC-model. Comparing NTCP modelling of SBRT data and data from breast cancer, lung cancer and whole lung irradiation implies that the response of the lung is treatment specific. More data are however needed in order to have a more reliable modelling.

A method to separate the rectum from the prostate during proton beam radiotherapy of prostate cancer patients

Abstract The use of protons for curative treatment of prostate cancer is increasing, either as a single treatment modality or in combination with conventional radiotherapy. The proximity between prostate (target) and rectum (organ at risk) often leads to a compromise between dose to target and organ at risk. Material and methods. The present study describes a method where the distance between prostate and rectum is increased by retraction of the rectum in dorsal direction. Comparative treatment plans with and without retraction of the rectum in the same patients have been studied. Nine patients with biopsy proven, localised adenocarcinoma of the prostate were studied. A cylindrical rod of Perspex was inserted into the rectum. This device allows the rectum to be retracted posteriorly. The patients were given a proton boost of 20 Gy in four fractions of 5 Gy in addition to a conventional photon beam treatment to a dose of 50 Gy in 25 fractions of 2 Gy. Results. Comparative treatment planning shows that the treatment plan with rectal retraction significantly reduces (p<0.01) the volume of the rectal wall receiving high doses (equal to 70 Gy in 2 Gy fractions) in all patients. Conclusions. The proton boost treatment with retraction of rectum during treatment decreases the rectal dose substantially. This is expected to reduce rectal side effects.

Practice patterns of photon and proton pediatric image guided radiation treatment: Results from an International Pediatric Research Consortium

PURPOSE Image guided radiation therapy (IGRT) has become common practice for both photon and proton radiation therapy, but there is little consensus regarding its application in the pediatric population. We evaluated clinical patterns of pediatric IGRT practice through an international pediatrics consortium comprised of institutions using either photon or proton radiation therapy. METHODS AND MATERIALS Seven international institutions with dedicated pediatric expertise completed a 53-item survey evaluating patterns of IGRT use in definitive radiation therapy for patients ≤21 years old. Two institutions use proton therapy for children and all others use IG photon therapy. Descriptive statistics including frequencies of IGRT use and means and standard deviations for planning target volume (PTV) margins by institution and treatment site were calculated. RESULTS Approximately 750 pediatric patients were treated annually across the 7 institutions. IGRT was used in tumors of the central nervous system (98%), abdomen or pelvis (73%), head and neck (100%), lung (83%), and liver (69%). Photon institutions used kV cone beam computed tomography and kV- and MV-based planar imaging for IGRT, and all proton institutions used kV-based planar imaging; 57% of photon institutions used a specialized pediatric protocol for IGRT that delivers lower dose than standard adult protocols. Immobilization techniques varied by treatment site and institution. IGRT was utilized daily in 45% and weekly in 35% of cases. The PTV margin with use of IGRT ranged from 2 cm to 1 cm across treatment sites and institution. CONCLUSIONS Use of IGRT in children was prevalent at all consortium institutions. There was treatment site-specific variability in IGRT use and technique across institutions, although practices varied less at proton facilities. Despite use of IGRT, there was no consensus of optimum PTV margin by treatment site. Given the desire to restrict any additional radiation exposure in children to instances where the exposure is associated with measureable benefit, prospective studies are warranted to optimize IGRT protocols by modality and treatment site.

Profile of European proton and carbon ion therapy centers assessed by the EORTC facility questionnaire

BACKGROUND We performed a survey using the modified EORTC Facility questionnaire (pFQ) to evaluate the human, technical and organizational resources of particle centers in Europe. MATERIAL AND METHODS The modified pFQ consisted of 235 questions distributed in 11 sections accessible on line on an EORTC server. Fifteen centers from 8 countries completed the pFQ between May 2015 and December 2015. RESULTS The average number of patients treated per year and per particle center was 221 (range, 40-557). The majority (66.7%) of centers had pencil beam or raster scanning capability. Four (27%) centers were dedicated to eye treatment only. An increase in the patients-health professional FTE ratio was observed for eye tumor only centers when compared to other centers. All centers treated routinely chordomas/chondrosarcomas, brain tumors and sarcomas but rarely breast cancer. The majority of centers treated pediatric cases with particles. Only a minority of the queried institutions treated non-static targets. CONCLUSIONS As the number of particle centers coming online will increase, the experience with this treatment modality will rise in Europe. Children can currently be treated in these facilities in a majority of cases. The majority of these centers provide state of the art particle beam therapy.

A comparison of patient position displacements from body surface laser scanning and cone beam CT bone registrations for radiotherapy of pelvic targets

Abstract Background and purpose. Optical surface detection has attractive features as a mean in radiotherapy for patient positioning tasks such as set-up, monitoring and gating. To aid in hitting radiotherapy targets the correlation between detected surface displacements and internal structure displacements is crucial. In this study, we compare set-up displacements derived from a body surface laser scanning (BSLS) system to displacements derived from bone registrations with a cone beam computed tomography (CBCT) system in order to quantify the accuracy and applicability of BSLS for fractionated treatments in the pelvic region. Material and methods. Displacements from concurrent BSLS and CBCT registrations were compared for 40 patients treated in the pelvic region for a total of 170 set-ups. Surface data captured by BSLS at the first treatment fraction (BSLSref) was used as main reference for the BSLS system, while bony structures from the planning CT were used as a reference for the CBCT method. As comparison, the patient outline extracted from the planning CT was used as BSLS reference (CTref). The displacements detected by the CBCT system (skin-marks-only) was also used for comparison. Results. The mean differences (± 1 SD) between the BSLS and CBCT displacements were −0.01 (± 0.17) cm, 0.00 (± 0.21) cm and 0.01 (± 0.17) cm in the lateral, longitudinal and vertical directions, respectively. The median length of the difference was 0.26 cm (0.24–0.29 cm, 95% CI). The median of the difference between CBCT and BSLS displacements based on CTref was 0.37 cm (0.30–0.39 cm) and the median for skin-marks-only was 0.38 cm (0.34–0.42 cm). Conclusions. The BSLS system is a good supplement to the CBCT system for accurate set-up for fractions when no CBCT is deemed necessary for pelvic targets. Inter-fractional skin movement in relation to bone was estimated to be 0.2 cm in the lateral (X), longitudinal (Y) and vertical direction (Z), respectively.

Comparative Proton and Photon Treatment Planning in Pediatric Patients with Various Diagnoses

Abstract Purpose: Radiation therapy with protons, owing to its physical properties, can be advantageous for the treatment of children. This study was conducted in order to quantify the advantages of proton therapy from a treatment planning point of view in a consecutive, realistic, and mixed pediatric/adolescent population with varying diagnoses and target locations. Patients and Methods: Forty-five patients treated with conventional 3-dimensional conformal radiation therapy photon radiation therapy were retrospectively re-planned with scanned proton beams. Treatment sites represented were the central nervous system, head and neck, thorax, and abdomen. Median age was 8 years (range, 2-18 years). All plans were optimized with intensity-modulated proton therapy (multi-field optimization). We analyzed a number of dose-volume descriptors for planned target volumes (PTVs). Organ-specific mean doses and relevant DV -values were derived for organs at risk. In addition, homogeneity index, conformity index, treate...