Andreas Hallqvist

SPACE – A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC

BACKGROUNDnStereotactic body radiotherapy (SBRT) has been introduced for small lung tumors due to excellent local control and few side effects, even though there are no comparative studies. SPACE (Stereotactic Precision And Conventional radiotherapy Evaluation) is the first randomized phase II trial comparing SBRT and conventional fractionated radiotherapy (3DCRT).nnnMETHODSnPatients with stage I medically inoperable NSCLC were randomized to receive SBRT to 66Gy in 3 fractions (one week) or 3DCRT to 70Gy (7weeks). Patients were followed to assess efficacy, toxicity and HRQL.nnnFINDINGSnBetween 2007 and 2011, 102 patients were randomized. Mean age 74 (57-86), 60% women, the vast majority (92%) had COPD or cardiovascular comorbidity. The SBRT arm included more patients with T2-tumors (p=0.02) and male gender (p=0.35). The median follow-up was 37months with a 1-, 2- and 3-year PFS of: SBRT: 76%, 53%, 42% and 3DCRT: 87%, 54% 42%, HR=0.85 (95% CI 0.52-1.36) with no difference between the groups and no difference in OS (HR=0.75, 95% CI 0.43-1.30). At the end of the study 70% of SBRT patients had not progressed compared to 59% (3DCRT, p=0.26). Toxicity was low with no grade 5 events. Pneumonitis of any grade was observed in 19% (SBRT) and 34% (3DCRT, p=0.26), and esophagitis in 8% and 30% respectively (p=0.006). HRQL was evaluated with the EORTC QLQ 30 and LC14 module and patients treated with 3DCRT experienced worse dyspnea (p=0.01), chest pain (p=0.02) and cough (>10 points difference).nnnINTERPRETATIONnThere was no difference in PFS and OS between SBRT and conventionally treated patients despite an imbalance of prognostic factors. We observed a tendency of an improved disease control rate in the SBRT group and they experienced better HRQL and less toxicity. SBRT is convenient for patients and should be considered standard treatment for patients with inoperable stage I NSCLC.

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

BACKGROUNDnSeveral 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.nnnMETHODSnBetween 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.nnnRESULTSnSeventy-one patients were eligible for analysis as four were incorrectly enrolled.nnnHISTOLOGYnadenocarcinoma 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%.nnnTOXICITYnesophagitis 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.nnnCONCLUSIONnInduction 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.

Health related quality of life in locally advanced NSCLC treated with high dose radiotherapy and concurrent chemotherapy or cetuximab - Pooled results from two prospective clinical trials

BACKGROUNDnIn non-small cell lung cancer (NSCLC) stage III, data on patient reported health-related quality of life (HRQL) are scarce, especially regarding concurrent chemoradiotherapy.nnnAIMSnTo evaluate HRQL in patients treated with high dose radiotherapy combined with concurrent chemotherapy or the antibody cetuximab.nnnMETHODSnThe study population comprised all patients enroled in either of two phase II trials in locally advanced NSCLC performed in Sweden 2002-2007. The RAKET trial investigated three different ways of increasing local control (accelerated hyperfractionated treatment or concurrent daily or weekly chemotherapy). The Satellite trial evaluated the addition of cetuximab to thoracic irradiation. HRQL was measured at four time points: At baseline, before radiotherapy, 4-6 weeks after radiotherapy and at 3 months follow-up, using the EORTC QLQ-C30 and LC14 set of questionnaires.nnnRESULTSn154/220 patients (65%) who completed HRQL assessments at all time points were included in the longitudinal study. There was a significant decline over time regarding most functioning measures. Dyspnoea and fatigue gradually deteriorated without recovery after completed treatment. Chemotherapy related symptoms showed a transient deterioration, whereas radiotherapy related esophagitis had not fully recovered at 3 months. Patients with stage IIIA disease tended to recover better regarding global QL, fatigue and dyspnoea compared to patients with stage IIIB. Patients with WHO performance status (PS) 0 reported improved global QL and less fatigue over time compared with PS 1. Concurrent chemotherapy was associated with more pronounced fatigue and dysphagia, and worse global QL compared with concurrent cetuximab. Baseline physical functioning was an independent predictor of overall survival.nnnCONCLUSIONnPatients undergoing high dose thoracic radiotherapy combined with chemotherapy or cetuximab reported a gradual deterioration in functioning, dyspnoea and fatigue, while treatment related side effects were transient. Radiotherapy with concurrent cetuximab had less negative impact on HRQL than concurrent chemoradiation.

How to improve loco-regional control in stages IIIa―b NSCLC? Results of a three-armed randomized trial from the Swedish Lung Cancer Study Group

BACKGROUNDnA combination of chemotherapy and radiotherapy is the treatment base for locally advanced non-small cell lung cancer (NSCLC). However, both loco-regional and distant failure is frequent. Attempts to improve the loco-regional control were made in three separate phase II studies in Swedish University Hospitals, where accelerated radiotherapy or concurrent daily or weekly chemotherapy with conventional radiotherapy were tested. Comparatively good results from these studies lead to this national randomized phase II study, the RAKET-study, where the different concepts were investigated on a wider basis for further phase III studies.nnnMETHODSnInoperable stage III non-small cell lung cancer patients in good performance status (PS<2) were equally randomized to either of three arms in eight institutions. All arms started with two cycles of induction chemotherapy: paclitaxel 200 mg/m2 and carboplatin AUC6. Arm A: a third identical cycle was given concomitant with start of accelerated radiotherapy, 1.7 Gy BID to 64.6 Gy in 4.5 weeks. Arm B consisted of daily concomitant paclitaxel 12 mg/m2 with conventionally fractionated radiotherapy: 2 Gy to 60 Gy in 6 weeks. Arm C: weekly concomitant paclitaxel 60 mg/m2 and identical radiotherapy to 60 Gy. Primary endpoint: TTP. Secondary: OS, toxicity, QL and relapse pattern.nnnRESULTSnBetween June 2002 and May 2005 152 patients were randomized and of them 151 were evaluable: 78 men and 73 women, median age 62 years (43-78), 55% had performance status 0 and 45% PS 1. Thirty-four percent had stage IIIa and 66% IIIb.nnnHISTOLOGYnadenocarcinoma 48%, squamous cell carcinoma 32% and 20% non-small cell carcinoma. The three arms were well balanced. Toxicity was manageable with 12% grades 3-4 esophagitis, 1% grades 3-4 pneumonitis and there was no clear difference between the arms. The QL data did not differ either. Median time to progression was 9.8 (8.3-12.7) months (8.8, 10.3 and 9.3 months for arms A, B and C, respectively). Median survival was 17.8 (14.4-23.7) months (17.7, 17.7 and 20.6 months for A, B and C, respectively). The 1-, 3- and 5-year overall survival was 63, 31 and 24%. Sixty-nine percent of the patients relapsed with distant metastases initially and 31% had loco-regional tumor progression, without significant differences between treatment arms. Thirty-four percent developed brain metastases.nnnCONCLUSIONSnTreatment results are quite equal by intensifying the loco-regional treatment either by accelerated fractionated radiotherapy or daily or weekly concomitant chemo-radiotherapy both in terms of survival, toxicity and quality of life. The optimal treatment schedule for patients with locally advanced NSCLC is still to be decided and investigated in future clinical studies. Relapse pattern with distant metastases and especially brain metastases is a great problem and need further research for better therapy options and higher cure rate for this patient group.

Positron emission tomography and computed tomographic imaging (PET/CT) for dose planning purposes of thoracic radiation with curative intent in lung cancer patients: A systematic review and meta-analysis

BACKGROUND AND PURPOSEnPET/CT is a proposed management to improve the accuracy of high dose radiochemotherapy in lung cancer patients. This systematic review was performed to investigate the possible impact on clinical outcome and to quantify the effect on patient selection and target definition.nnnMATERIAL AND METHODSnSystematic literature searches were conducted, eligible full-text articles were assessed for quality and data were extracted.nnnRESULTSnThirty-five cross-sectional studies and one observational study fulfilled the inclusion criteria. No randomized trials or data with regard to clinical endpoints were found. The summary estimates of a change in target definition were 36% in patients with a former staging PET, and 43% and 26% in patients without a staging PET, for non small- and small cell lung cancer respectively. The corresponding summary estimates of a change in treatment intent from curative to palliative treatment were 20% and 22% and 9% respectively.nnnCONCLUSIONnPET/CT for dose planning improves target definition and patient selection. Approximately two in five patients had a significant change in target definition and one in five received palliative treatment instead. The proportions seem to be similar regardless of the availability of a previous staging-PET.

Accelerated hyperfractionated radiotherapy and concomitant chemotherapy in small cell lung cancer limited-disease. Dose response, feasibility and outcome for patients treated in western Sweden, 1998–2004.

Addition of thoracic radiation therapy (TRT) to chemotherapy (CHT) can increase overall survival in patients with small cell lung cancer limited-disease (SCLC-LD). Accelerated fractionation and early concurrent platinum-based CHT, in combination with prophylactic cranial irradiation, represent up-front treatment for this group of patients. Optimised and tailored local and systemic treatment is important. These concepts were applied when a new regional treatment programme was designed at Sahlgrenska University Hospital in 1997. The planned treatment consisted of six courses of CHT (carboplatin/etoposide)+TRT±prophylactic cranial irradiation (PCI). Standard TRT was prescribed as 1.5 Gy BID to a total of 60 Gy during 4 weeks, starting concomitantly with the second or third course of CHT. However, patients with large tumour burdens, poor general condition and/or poor lung function received 45 Gy, 1.5 Gy BID, during 3 weeks. PCI in 15 fractions to a total dose of 30 Gy was administered to all patients with complete remission (CR) and “good” partial remission (PR) at response evaluation. Eighty consecutive patients were treated between January 1998 and December 2004. Forty-six patients were given 60 Gy and 34 patients 45 Gy. Acute toxicity occurred as esophagitis grade III (RTOG/EORTC) in 16% and as pneumonitis grade I–II in10%. There were no differences in toxicity between the two groups. Three- and five-year overall survival was 25% and 16%, respectively. Median survival was 20.8 months with no significant difference between the two groups. In conclusion, TRT with a total dose of 60 or 45 Gy is feasible with comparable toxicity and no difference in local control or survival. Distant metastasis is the main cause of death in this disease; the future challenge is thus further improvement of the systemic therapy combined with optimised local TRT.

The prognostic value of pre-treatment thrombocytosis in two cohorts of patients with non-small cell lung cancer treated with curatively intended chemoradiotherapy

Chemoradiotherapy is the standard of care for inoperable stage III non-small cell lung cancer (NSCLC). This treatment, however, offers only a small chance of cure and is associated with many side effects. Little research has been made concerning which patients benefit most/least from the treatment. The present study evaluates the prognostic value of anemia, leukocytosis and thrombocytosis at diagnosis in this treatment setting. In the present study, data were collected retrospectively for 222 patients from two different phase II studies conducted between 2002-2007 in Sweden with patients treated with chemoradiotherapy for stage IIIA-IIIB NSCLC. Clinical data and the serum values of hemoglobin (Hgb), White blood cells (WBC) and Platelets (Plt) at enrollment were collected for all patients and studied in relation to overall survival using Kaplan-Meier product-limit estimates and a multivariate Cox proportional hazards regression model. The results showed that patients with thrombocytosis (Plt > 350 x 109/L) had a shorter median overall survival (14.5 months) than patients with normal Plt at baseline (23.7 months). Patients with leukocytosis (WBC > 9 x 109/L) had a shorter median survival (14.9 months) than patients with a normal WBC at baseline (22.5 months). However, in a multivariate model including all lab parameters and clinical factors, only thrombocytosis and performance status displayed a prognostic significance. In Conclusion, thrombocytosis showed to be an independent prognostic marker associated with shorter overall survival in stage III NSCLC treated with curatively intended chemoradiotherapy. This knowledge can potentially be used together with established prognostic factors, such as performance status when choosing the optimal therapy for the individual patient in this clinical setting.

An automated Monte Carlo QC system for volumetric modulated arc therapy: Possibilities and challenges

PURPOSEnTo develop and implement an automated Monte Carlo (MC) system for patient specific VMAT quality control in a patient geometry that generates treatment planning system (TPS) compliant DICOM objects and includes a module for 3D analysis of dose deviations. Also, the aims were to recommend diagnose specific tolerance criteria and an evaluation procedure.nnnMETHODSnThe EGSnrc code package formed the basis for development of the MC system. The workflow consists of a number of modules connected to a TPS by means of manual DICOM exports and imports which were executed sequentially without user interaction. DVH comparison was performed in the TPS. In addition, MC- and TPS dose distributions were analysed by applying the normalized dose difference (NDD) formalism. NDD failure maps and a pass rate for a certain threshold were obtained. 170 clinical plans (prostate, thorax, head-and-neck and gynecological) were selected for analysis.nnnRESULTSnAgreement within 1.5% was found between clinical- and MC data for the mean dose to the target volumes and within 3% for parameters more sensitive to the shape of the DVH e.g. D98% PTV. Regarding the NDD analysis, tolerance criteria 2%/3u202fmm were established for prostate plans and 3%/3u202fmm for the rest of the cases.nnnCONCLUSIONSnAn automated MC system was developed and implemented. Evaluation procedure is recommended with NDD-analysis as a first step. For pass rateu202f<u202f95%, the evaluation continues with comparison of DVH parameters. For deviations larger than 2%, a visual inspection of the clinical- and MC dose distributions is performed.

Dose escalation to 84 Gy with concurrent chemotherapy in stage III NSCLC appears excessively toxic: Results from a prematurely terminated randomized phase II trial

OBJECTIVESnConcurrent chemoradiotherapy is the mainstay treatment for NSCLC stage III disease. To investigate whether radiation dose escalation based on individual normal tissue constraints can improve outcome, the Swedish lung cancer study group launched this randomized phase II trial.nnnMATERIALS AND METHODSnNSCLC patients with stage III disease, good performance status (0-1) and adequate lung function (FEV1u202f>u202f1.0u202fL and CO diffusion capacity > 40%) received three cycles of cisplatin (75u202fmg/m2 day 1) and vinorelbine (25u202fmg/m2 day 1 and 8) every third week. Radiotherapy started concurrently with the second cycle, with either 2u202fGy daily, 5 days a week, to 68u202fGy (A) or escalated therapy (B) based on constraints to the spinal cord, esophagus and lungs up to 84u202fGy by adding an extra fraction of 2u202fGy per week.nnnRESULTSnA pre-planned safety analysis revealed excessive toxicity and decreased survival in the escalated arm, and the study was stopped. Thirty-six patients were included during 2011-2013 (56% male, 78% with adenocarcinoma, 64% with PS 0 and 53% with stage IIIB). The median progression-free survival (PFS) and overall survival (OS) were 11 and 17 months in arm B compared to the encouraging results of 28 and 45 months in the standard arm. The 1- and 3-year survival rates were 56% and 33% (B) and 72% and 56% (A), respectively. There were seven toxicity-related deaths due to esophageal perforations and pneumonitis: five in the escalated group and two with standard treatment.nnnCONCLUSIONnDose-escalated concurrent chemoradiotherapy to 84u202fGy to primary tumor and nodal disease is hazardous, with a high risk of excessive toxicity, whereas modern standard dose chemoradiotherapy with proper staging given in the control arm shows a promising outcome with a median survival of 45 months and a 3-year survival of 56% (NCT01664663).

Positron emission tomography and computed tomographic (PET/CT) imaging for radiation therapy planning in anal cancer: A systematic review and meta-analysis

To improve the accuracy of chemoradiation therapy in anal cancer patients PET/CT is frequently used in the planning of radiation therapy. A systematic review was performed to assess impact on survival, quality of life, symptom score, change in target definition and treatment intention. Systematic literature searches were conducted in Medline, EMBASE, the Cochrane Library, and Centre for Reviews and Dissemination. Ten cross-sectional studies were identified. No data were available on survival or quality of life. The summary estimate of the proportion of patients in which PET/CT had an impact on the target definition, was 23% (95% CI 16;33). The corresponding summary estimate of a change in treatment intent from curative to palliative was 3% (95% CI 2;6). Almost one in four patients had a change in target definition, which supports the use of PET/CT in radiation therapy planning, but the consequence regarding survival and quality of life is still uncertain.